ClinVar contains an entry for this variant (Variation ID: 552712). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of this splice site alters HBB gene expression (PMID: 6583702). Disruption of this splice site has been observed in individuals with autosomal recessive beta-thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the HBB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.316-1G>A
Germline
Classification
Help
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.
(7)
Help
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.
Pathogenic/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000518.5(HBB):c.316-1G>A
Variation ID: 552712 Accession: VCV000552712.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5225727 (GRCh38) [ NCBI UCSC ] 11: 5246957 (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 May 9, 2018 Jul 15, 2024 Apr 5, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.316-1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice acceptor NC_000011.10:g.5225727C>T NC_000011.9:g.5246957C>T NG_000007.3:g.71889G>A NG_046672.1:g.3662C>T NG_053049.1:g.2048C>T NG_059281.1:g.6345G>A LRG_1232:g.6345G>A LRG_1232t1:c.316-1G>A - Protein change
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- Other names
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IVS-II-850 G>A
IVS II-850 (G>A)
IVS2AS, G-A, -1
- Canonical SPDI
- NC_000011.10:5225726:C:T
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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.
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- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| HBB | - | - |
GRCh38 GRCh37 |
22 | 1834 | |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
| LOC110006319 | - | - | - | GRCh38 | - | 984 |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 5, 2024 | RCV000668023.6 | |
| Pathogenic (2) |
no assertion criteria provided
|
Jan 1, 2018 | RCV000736022.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 25, 2023 | RCV003558495.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Aug 22, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000792565.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
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Pathogenic
(Feb 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004294093.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 552712). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus … (more)
ClinVar contains an entry for this variant (Variation ID: 552712). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of this splice site alters HBB gene expression (PMID: 6583702). Disruption of this splice site has been observed in individuals with autosomal recessive beta-thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the HBB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. (less)
|
|
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Likely pathogenic
(Apr 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370574.2
First in ClinVar: Jul 16, 2020 Last updated: Jul 15, 2024 |
Comment:
Variant summary: HBB c.316-1G>A (also described in the literature as IVS-II-850G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting … (more)
Variant summary: HBB c.316-1G>A (also described in the literature as IVS-II-850G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251150 control chromosomes (gnomAD). c.316-1G>A has been reported in the literature in homozygous and heterozygous individuals affected with beta-thalassemia (e.g. Al Mosawi_2020). Furthermore, beta-thal trait individuals heterozygous for the variant, were reported with a history of mild anemia and microcytosis (e.g. Curuk_1995, Knott_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the same splice-site nucleotide (c.316-1G>C, c.316-1G>T) have been reported internally and also, in ClinVar and HGMD as pathogenic/likely pathogenic and disease-associated. The following publications have been ascertained in the context of this evaluation (PMID: 31714438, 7558878, 16466947, 9101288). ClinVar contains an entry for this variant (Variation ID: 552712). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(May 01, 1995)
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no assertion criteria provided
Method: literature only
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BETA-ZERO-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000037079.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
Curuk et al. (1995) described an American family of English-Scottish descent in which 6 members were found to be heterozygous for beta-thalassemia (613985). Sequencing of … (more)
Curuk et al. (1995) described an American family of English-Scottish descent in which 6 members were found to be heterozygous for beta-thalassemia (613985). Sequencing of the HBB gene showed a G-to-A transition at the splice acceptor site of the second intron, changing the canonical AG to AA. Nucleotide 850 was involved; Curuk et al. (1995) commented that a G-to-C change in the same nucleotide had been found in a Yugoslavian family, whereas a frameshift due to deletion of nucleotide 850 was found in an Italian family. All 3 nucleotide changes lead to beta-zero thalassemia and are rare in the populations in which they were discovered. (less)
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Pathogenic
(Jul 01, 2018)
|
no assertion criteria provided
Method: research
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beta Thalassemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
College of Science, Al Muthanna University, Al Muthanna University
Accession: SCV000804462.1
First in ClinVar: Mar 19, 2019 Last updated: Mar 19, 2019 |
Number of individuals with the variant: 2
Age: 8-10 years
Sex: female
Ethnicity/Population group: Arabic Iraqi
Geographic origin: Iraq
Method: The method has combined gap PCR (an amplification reaction for which primers flank the Δ619 deletion site to recognize this deletion mutation with Sanger DNA sequencing), which used primers to recognize common mutations of β-thalassemia alleles targeted the populations in Middle East population.
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Pathogenic
(Jan 01, 2018)
|
no assertion criteria provided
Method: research
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beta^0^ Thalassemia
Affected status: yes
Allele origin:
germline
|
College of Science, Al Muthanna University, Al Muthanna University
Accession: SCV000864065.1
First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 |
Age: 11-17 years
Sex: mixed
Ethnicity/Population group: Arabic Iraqi
Geographic origin: Iraq
|
|
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Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244415.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
Comment:
Comment:
Variant summary: HBB c.316-1G>A (also described in the literature as IVS-II-850G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251150 control chromosomes (gnomAD). c.316-1G>A has been reported in the literature in homozygous and heterozygous individuals affected with beta-thalassemia (e.g. Al Mosawi_2020). Furthermore, beta-thal trait individuals heterozygous for the variant, were reported with a history of mild anemia and microcytosis (e.g. Curuk_1995, Knott_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the same splice-site nucleotide (c.316-1G>C, c.316-1G>T) have been reported internally and also, in ClinVar and HGMD as pathogenic/likely pathogenic and disease-associated. The following publications have been ascertained in the context of this evaluation (PMID: 31714438, 7558878, 16466947, 9101288). ClinVar contains an entry for this variant (Variation ID: 552712). Based on the evidence outlined above, the variant was classified as likely pathogenic.
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. |
Comment:
ClinVar contains an entry for this variant (Variation ID: 552712). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of this splice site alters HBB gene expression (PMID: 6583702). Disruption of this splice site has been observed in individuals with autosomal recessive beta-thalassemia (PMID: 2123063, 6583702). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 2 of the HBB gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.
Comment:
Variant summary: HBB c.316-1G>A (also described in the literature as IVS-II-850G>A) is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251150 control chromosomes (gnomAD). c.316-1G>A has been reported in the literature in homozygous and heterozygous individuals affected with beta-thalassemia (e.g. Al Mosawi_2020). Furthermore, beta-thal trait individuals heterozygous for the variant, were reported with a history of mild anemia and microcytosis (e.g. Curuk_1995, Knott_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Other variants affecting the same splice-site nucleotide (c.316-1G>C, c.316-1G>T) have been reported internally and also, in ClinVar and HGMD as pathogenic/likely pathogenic and disease-associated. The following publications have been ascertained in the context of this evaluation (PMID: 31714438, 7558878, 16466947, 9101288). ClinVar contains an entry for this variant (Variation ID: 552712). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical Laboratory Manifestation and Molecular Diagnosis of β-Thalassemia Patients in Iraq. | AlMosawi RHN | Journal of pediatric hematology/oncology | 2020 | PMID: 31714438 |
| Tetra-Primer ARMS PCR Optimization for Detection of IVS-II-I (G-A) and FSC 8/9 InsG Mutations in β-Thalassemia Major Patients in Isfahan Population. | Hajihoseini S | Iranian journal of public health | 2015 | PMID: 25905082 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Novel and Mediterranean beta thalassemia mutations in the indigenous Northern Ireland population. | Knott M | Blood cells, molecules & diseases | 2006 | PMID: 16466947 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| beta-thalassemia mutations in Japanese and Koreans. | Ohba Y | Hemoglobin | 1997 | PMID: 9101288 |
| A newly discovered beta O-thalassemia (IVS-II-850, G-->A) mutation in a north European family. | Cürük MA | Hemoglobin | 1995 | PMID: 7558878 |
| Compound heterozygosity for a mild beta (+) and a rare beta(0)-thalassemia allele. | Codrington J | Acta haematologica | 1990 | PMID: 2123063 |
| beta-Thalassemia in American Blacks: novel mutations in the "TATA" box and an acceptor splice site. | Antonarakis SE | Proceedings of the National Academy of Sciences of the United States of America | 1984 | PMID: 6583702 |
| https://ithanet.eu/db/ithagenes?ithaID=226 | - | - | - | - |
Text-mined citations for rs33952266 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.