ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.82G>T (p.Ala28Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.82G>T (p.Ala28Ser)
Variation ID: 15239 Accession: VCV000015239.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5226940 (GRCh38) [ NCBI UCSC ] 11: 5248170 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 29, 2015 Apr 15, 2024 Apr 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.82G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000509.1:p.Ala28Ser missense NC_000011.10:g.5226940C>A NC_000011.9:g.5248170C>A NG_000007.3:g.70676G>T NG_042296.1:g.471C>A NG_046672.1:g.4875C>A NG_059281.1:g.5132G>T LRG_1232:g.5132G>T LRG_1232t1:c.82G>T LRG_1232p1:p.Ala28Ser P68871:p.Ala28Ser - Protein change
- A28S
- Other names
- A27S
- cd27 G>T
- CD 27 GCC>TCC [Ala>Ser]
- Canonical SPDI
- NC_000011.10:5226939:C:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HBB | - | - |
GRCh38 GRCh37 |
21 | 1815 | |
LOC106099062 | - | - | - | GRCh38 | - | 849 |
LOC107133510 | - | - | - | GRCh38 | - | 1767 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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other (1) |
no assertion criteria provided
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Dec 12, 2017 | RCV000016439.4 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1989 | RCV000016440.28 | |
Pathogenic (1) |
no assertion criteria provided
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Jan 1, 1989 | RCV000016441.28 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jul 22, 2021 | RCV000169609.8 | |
Pathogenic (2) |
criteria provided, single submitter
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May 2, 2018 | RCV000780311.2 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001004353.1 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV000757368.19 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 4, 2024 | RCV003992156.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(May 02, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hemoglobinopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917478.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: HBB c.82G>T (p.Ala28Ser) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of … (more)
Variant summary: HBB c.82G>T (p.Ala28Ser) results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Although 5/5 computational tools predict no significant impact on normal splicing, all 5 tools predict the presence of a cryptic 5' donor site upstream of the canonical splice site. These predictions are supported by a study that showed the presence of an alternative transcript for c.82G>T (Orkin_1984). The variant allele was found at a frequency of 1.2e-05 in 247346 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in HBB causing Beta Thalassemia (1.2e-05 vs 1.10e-02), allowing no conclusion about variant significance. The variant, c.82G>T, has been reported in the literature in multiple individuals affected with Beta Thalassemia (Orkin_1984, Baklouti_1986, El-Kalla_1997, Tadmouri_1998, Sirdah_2013, Nasouhipur_2014). Clinical presentation ranged from mild to severe b-thal intermedia with a varying need for transfusions depending on the second pathogenic allele found. Based on the published reports, most cases have been diagnosed relatively late in childhood or puberty and some are much later in adulthood. Oxygen affinity studies showed a significantly decreased affinity for p.A28S for both heterozygous carriers and Hb Knossos-b-thalassemia compound heterozygotes (Fessas_1986). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Hb SS disease
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001163288.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
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Likely pathogenic
(Feb 16, 2015)
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criteria provided, single submitter
Method: literature only
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beta Thalassemia
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000221131.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Mar 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003919670.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
Published functional studies demonstrate a damaging effect as RNA transcripts are abnormally processed (Orkin et al., 1984); In silico analysis supports that this missense variant … (more)
Published functional studies demonstrate a damaging effect as RNA transcripts are abnormally processed (Orkin et al., 1984); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25155404, 19429541, 25087612, 25332589, 3955238, 17949282, 26754299, 31553106, 3942130, 6469698, 28399358, 2467892, 9223924, 30777047, 6733281) (less)
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Pathogenic
(Jun 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000885562.4
First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024 |
Comment:
The Hb Knossos variant (HBB: c.82G>T; p.Ala28Ser, also known as Ala27Ser when numbered from the mature protein, rs35424040, HbVar ID: 281) has been reported in … (more)
The Hb Knossos variant (HBB: c.82G>T; p.Ala28Ser, also known as Ala27Ser when numbered from the mature protein, rs35424040, HbVar ID: 281) has been reported in multiple unrelated individuals diagnosed with thalassemia intermedia (Altay 1990, Fessas 1982, Orkin 1984, Sirdah 2013), often found in-trans with other pathogenic HBB variants (Altay 1990, Orkin 1984, Sirdah 2013, HbVar and references therein). This variant is listed in ClinVar (Variation ID: 15239), and found in the general population with an overall allele frequency of 0.001% (3/251362 alleles) in the Genome Aggregation Database. Computational analyses predict that the variant activates a nearby cryptic splice donor upstream of the canonical splice site (Alamut v.2.11). Functional studies detected the presence of aberrant mRNA in cells expressing the variant, with a transcript size that is consistent with utilization of the cryptic splice donor predicted by computational algorithms (Orkin 1984). Based on available information, the Hb Knossos variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Altay C et al. Beta-thalassemia intermedia in Turkey. Ann N Y Acad Sci. 1990; 612:81-9. PMID: 2291577 Fessas P et al. 'Silent' beta-thalassaemia caused by a 'silent' beta-chain mutant: the pathogenesis of a syndrome of thalassaemia intermedia. Br J Haematol. 1982; 51(4):577-83. PMID: 7104238 Orkin S et al. Abnormal processing of beta Knossos RNA. Blood. 1984; 64(1):311-3. PMID: 6733281 Sirdah M et al. The spectrum of B-thalassemia mutations in Gaza Strip, Palestine. Blood Cells Mol Dis. 2013; 50(4):247-51. PMID: 23321370 (less)
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Pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810472.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Jun 23, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002774342.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same … (more)
The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. (less)
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000942026.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 28 of the HBB protein (p.Ala28Ser). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 28 of the HBB protein (p.Ala28Ser). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs35424040, gnomAD 0.007%). This missense change has been observed in individual(s) with beta-thalassemia major or intermedia (PMID: 2467892, 6469698, 9223924, 17949282). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Hb Knossos, Cd27, and Ala27Ser. ClinVar contains an entry for this variant (Variation ID: 15239). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 6733281). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Malaria, susceptibility to
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809974.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
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Pathogenic
(Jan 01, 1989)
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no assertion criteria provided
Method: literature only
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BETA-KNOSSOS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036709.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al. (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin Knossos is … (more)
See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al. (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin Knossos is a cause of beta-thalassemia (613985), as is hemoglobin E. Orkin et al. (1984) isolated the beta(Knossos) gene and examined its expression in HeLa cells. Using a cryptic splice sequence that is enhanced by the Knossos substitution, they found that some beta(Knossos) transcripts were abnormally processed. In addition to Hb E, a silent substitution at beta 24 causes thalassemia by abnormal RNA processing. (less)
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Pathogenic
(Jan 01, 1989)
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no assertion criteria provided
Method: literature only
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BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036708.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al. (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin Knossos is … (more)
See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al. (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin Knossos is a cause of beta-thalassemia (613985), as is hemoglobin E. Orkin et al. (1984) isolated the beta(Knossos) gene and examined its expression in HeLa cells. Using a cryptic splice sequence that is enhanced by the Knossos substitution, they found that some beta(Knossos) transcripts were abnormally processed. In addition to Hb E, a silent substitution at beta 24 causes thalassemia by abnormal RNA processing. (less)
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other
(Dec 12, 2017)
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no assertion criteria provided
Method: literature only
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HEMOGLOBIN KNOSSOS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000036707.4
First in ClinVar: Apr 04, 2013 Last updated: Mar 25, 2018 |
Comment on evidence:
See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al. (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin Knossos is … (more)
See Arous et al. (1982), Rouabhi et al. (1983), Galacteros et al. (1984), Elwan et al. (1987), and Kutlar et al. (1989). Hemoglobin Knossos is a cause of beta-thalassemia (613985), as is hemoglobin E. Orkin et al. (1984) isolated the beta(Knossos) gene and examined its expression in HeLa cells. Using a cryptic splice sequence that is enhanced by the Knossos substitution, they found that some beta(Knossos) transcripts were abnormally processed. In addition to Hb E, a silent substitution at beta 24 causes thalassemia by abnormal RNA processing. (less)
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Pathogenic
(Nov 25, 2019)
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no assertion criteria provided
Method: curation
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244425.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Hemoglobinopathy
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001453788.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000537296.3
First in ClinVar: Mar 29, 2015 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Beta-Thalassemia. | Adam MP | - | 2024 | PMID: 20301599 |
Improvements in phenotype studies of hemoglobin disorders brought by advances in reversed-phase chromatography of globin chains. | Riou J | International journal of laboratory hematology | 2015 | PMID: 25130136 |
Hb Knossos: HBB:c.82G>T Associated with HBB:c.315+1G>A Beta Zero Mutation Causes Thalassemia Intermedia. | Nasouhipur H | Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion | 2014 | PMID: 25332589 |
Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. | Tabor HK | American journal of human genetics | 2014 | PMID: 25087612 |
The spectrum of β-thalassemia mutations in Gaza Strip, Palestine. | Sirdah MM | Blood cells, molecules & diseases | 2013 | PMID: 23321370 |
Impact of single nucleotide polymorphisms in HBB gene causing haemoglobinopathies: in silico analysis. | George Priya Doss C | New biotechnology | 2009 | PMID: 19429541 |
Combination of Hb Knossos [Cod 27 (G-T)] and IVSII-745 (C-G) in a Turkish patient with beta-thalassemia major. | Keser I | Genetic testing | 2007 | PMID: 17949282 |
Molecular and population genetic analyses of beta-thalassemia in Turkey. | Tadmouri GO | American journal of hematology | 1998 | PMID: 9495372 |
[Beta thalassemia in Germany: molecular genetics and clinical phenotype in immigrant and in the native population]. | Schwarz C | Klinische Padiatrie | 1997 | PMID: 9340427 |
Compound heterozygosity for hemoglobin Knossos [alpha 2 beta 2 27 (B9) Ala-Ser] and IVS I-1 mutation. | Gürgey A | The Turkish journal of pediatrics | 1997 | PMID: 9223924 |
A significant beta-thalassemia heterogeneity in the United Arab Emirates. | el-Kalla S | Hemoglobin | 1997 | PMID: 9140720 |
Molecular characterization of beta-thalassemia in north Jordan. | Sadiq MF | Hemoglobin | 1994 | PMID: 7852087 |
A novel delta 0 mutation in cis with Hb Knossos: a study of different genetic interactions in three Egyptian families. | Olds RJ | British journal of haematology | 1991 | PMID: 1873227 |
Beta-thalassemia intermedia in Turkey. | Altay C | Annals of the New York Academy of Sciences | 1990 | PMID: 2291577 |
Beta-thalassemia intermedia in two Turkish families is caused by the interaction of Hb Knossos [beta 27(B9)Ala----Ser] and of Hb City of Hope [beta 69(E13)Gly----ser] with beta (0)-thalassemia. | Kutlar A | Hemoglobin | 1989 | PMID: 2467892 |
Hemoglobin Knossos [alpha 2 beta 2(27)(B9)Ala----Ser] in Egypt. | Elwan S | Hemoglobin | 1987 | PMID: 3114175 |
Homozygous hemoglobin Knossos (alpha 2 beta 227(B9) Ala----Ser): a new variety of beta (+)-thalassemia intermedia associated with delta (0)-thalassemia. | Baklouti F | Blood | 1986 | PMID: 3955238 |
Hemoglobin Knossos: a clinical, laboratory, and epidemiological study. | Fessas P | American journal of hematology | 1986 | PMID: 3942130 |
Abnormal processing of beta Knossos RNA. | Orkin SH | Blood | 1984 | PMID: 6733281 |
Two new cases of heterozygosity for hemoglobin Knossos alpha 2 beta 2 27 Ala----Ser detected in the French West Indies and Algeria. | Galacteros F | Hemoglobin | 1984 | PMID: 6469698 |
Silent beta-thalassemia associated with Hb Knossos beta 27 (B9) Ala replaced by Ser in Algeria. | Rouabhi F | Hemoglobin | 1983 | PMID: 6668188 |
Hb Knossos, beta 27 Ala leads to Ser (B 9): a new hemoglobinopathy presenting as a silent beta-thalassemia. | Rosa J | Progress in clinical and biological research | 1983 | PMID: 6664996 |
Structural study of hemoglobin Knossos, beta 27 (B9) Ala leads to Ser. A new abnormal hemoglobin present as a silent beta-thalassemia. | Arous N | FEBS letters | 1982 | PMID: 7173395 |
'Silent' beta-thalassaemia caused by a 'silent' beta-chain mutant: the pathogenesis of a syndrome of thalassaemia intermedia. | Fessas P | British journal of haematology | 1982 | PMID: 7104238 |
https://ithanet.eu/db/ithagenes?ithaID=91 | - | - | - | - |
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Text-mined citations for rs35424040 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.