This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs33915217, gnomAD 0.0009%). This variant has been observed in individuals with beta-thalassemia (PMID: 2439149). ClinVar contains an entry for this variant (Variation ID: 15448). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternate splicing and introduces a premature termination codon (PMID: 2439149). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.92+5G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2200760, 3021139, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.92+5G>T
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000518.5(HBB):c.92+5G>T
Variation ID: 15448 Accession: VCV000015448.103
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11p15.4 11: 5226925 (GRCh38) [ NCBI UCSC ] 11: 5248155 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 4, 2013 Feb 20, 2024 Dec 6, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000518.5:c.92+5G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000011.10:g.5226925C>A NC_000011.9:g.5248155C>A NG_000007.3:g.70691G>T NG_042296.1:g.456C>A NG_046672.1:g.4860C>A NG_059281.1:g.5147G>T LRG_1232:g.5147G>T LRG_1232t1:c.92+5G>T - Protein change
- -
- Other names
-
IVS I-5 (G>T)
IVS1, G-T, +5
- Canonical SPDI
- NC_000011.10:5226924:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00120 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- 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 | |
| LOC106099062 | - | - | - | GRCh38 | - | 862 |
| LOC107133510 | - | - | - | GRCh38 | - | 1784 |
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 (1) |
no assertion criteria provided
|
Mar 1, 1989 | RCV000016706.36 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 18, 2011 | RCV000030005.10 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 6, 2023 | RCV000505898.23 | |
| Pathogenic (3) |
no assertion criteria provided
|
Nov 25, 2019 | RCV000984182.13 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000601329.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 01, 2022 |
|
|
|
Pathogenic
(Dec 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002152639.3
First in ClinVar: Apr 11, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. … (more)
This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs33915217, gnomAD 0.0009%). This variant has been observed in individuals with beta-thalassemia (PMID: 2439149). ClinVar contains an entry for this variant (Variation ID: 15448). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternate splicing and introduces a premature termination codon (PMID: 2439149). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.92+5G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2200760, 3021139, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Apr 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000603942.7
First in ClinVar: Sep 30, 2017 Last updated: Feb 20, 2024 |
Comment:
The HBB c.92+5G>T variant (rs33915217, HbVar ID: 825), also known as IVS-I-5 (G->T), has been reported in the homozygous or compound heterozygous state in several … (more)
The HBB c.92+5G>T variant (rs33915217, HbVar ID: 825), also known as IVS-I-5 (G->T), has been reported in the homozygous or compound heterozygous state in several individuals affected with beta(+) thalassemia (Atweh 1987, HbVar database and references therein). Functional studies indicate that the variant causes aberrant splicing of the HBB transcript and reduction of full-length mRNA (Atweh 1987). The variant is listed as pathogenic in ClinVar (Variation ID: 15448), and observed once in the Genome Aggregation Database (1/251204 alleles). Consistent with functional studies, computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, the variant c.92+5G>T is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Atweh G et al. A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. Blood. 1987; 70(1):147-51. PMID: 2439149. (less)
|
|
|
pathogenic
(Aug 18, 2011)
|
criteria provided, single submitter
Method: curation, clinical testing
|
Beta Thalassemia Major
(autosomal recessive)
Affected status: yes, unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052660.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 11, 2022 |
Comment:
Converted during submission to Pathogenic.
Observation 1:
Number of individuals with the variant: 20
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 2
Observation 4:
Tissue: Blood
|
|
|
Pathogenic
(Jun 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002496220.3
First in ClinVar: Apr 11, 2022 Last updated: Jul 01, 2023 |
Comment:
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious … (more)
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348723, 22975760, 25525159, 9163586, 2577233, 2439149, 33092414) (less)
|
|
|
Pathogenic
(Mar 01, 1989)
|
no assertion criteria provided
Method: literature only
|
BETA-PLUS-THALASSEMIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000036976.2
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
This mutation is a cause of beta-plus-thalassemia (613985). A G-to-T change at position 5 of the donor site consensus sequence of IVS1 (CAG-gttggt-to-CAG-gttgtt) was found … (more)
This mutation is a cause of beta-plus-thalassemia (613985). A G-to-T change at position 5 of the donor site consensus sequence of IVS1 (CAG-gttggt-to-CAG-gttgtt) was found in a Mediterranean patient and an Anglo-Saxon patient by Atweh et al. (1987) and in an American black by Gonzalez-Redondo et al. (1988). The 2 cases of Atweh et al. (1987) were in different RFLP backgrounds, suggesting that they represented independent mutations. Atweh et al. (1987) showed that after transfer of the cloned genes into HeLa cells, followed by transient expression, partial inactivation of the normal donor splice site of IVS1 and activation of 2 major and 1 minor cryptic splice sites occur. The effects of this mutation on mRNA splicing were similar to those of another beta-thalassemia gene with a G-to-C transition at the same position (141900.0357). In a rare case of beta-thalassemia in a German family, Eigel et al. (1989) found a G-to-T transversion at the intron 1 donor site of the beta-globin gene. This may be the same mutation. The patient was homozygous for this mutation and had died at age 27 of heart failure resulting from iron overload. (less)
|
|
|
Pathogenic
(Sep 03, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV001132216.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
|
|
|
Pathogenic
(Nov 25, 2019)
|
no assertion criteria provided
Method: curation
|
beta Thalassemia
Affected status: unknown
Allele origin:
germline
|
The ITHANET community portal, The Cyprus Institute of Neurology and Genetics
Accession: SCV001244507.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Beta thalassemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002089239.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
The HBB c.92+5G>T variant (rs33915217, HbVar ID: 825), also known as IVS-I-5 (G->T), has been reported in the homozygous or compound heterozygous state in several individuals affected with beta(+) thalassemia (Atweh 1987, HbVar database and references therein). Functional studies indicate that the variant causes aberrant splicing of the HBB transcript and reduction of full-length mRNA (Atweh 1987). The variant is listed as pathogenic in ClinVar (Variation ID: 15448), and observed once in the Genome Aggregation Database (1/251204 alleles). Consistent with functional studies, computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, the variant c.92+5G>T is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Atweh G et al. A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. Blood. 1987; 70(1):147-51. PMID: 2439149.
Comment:
Converted during submission to Pathogenic.
Comment:
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348723, 22975760, 25525159, 9163586, 2577233, 2439149, 33092414)
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:
This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs33915217, gnomAD 0.0009%). This variant has been observed in individuals with beta-thalassemia (PMID: 2439149). ClinVar contains an entry for this variant (Variation ID: 15448). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternate splicing and introduces a premature termination codon (PMID: 2439149). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.92+5G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2200760, 3021139, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
The HBB c.92+5G>T variant (rs33915217, HbVar ID: 825), also known as IVS-I-5 (G->T), has been reported in the homozygous or compound heterozygous state in several individuals affected with beta(+) thalassemia (Atweh 1987, HbVar database and references therein). Functional studies indicate that the variant causes aberrant splicing of the HBB transcript and reduction of full-length mRNA (Atweh 1987). The variant is listed as pathogenic in ClinVar (Variation ID: 15448), and observed once in the Genome Aggregation Database (1/251204 alleles). Consistent with functional studies, computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, the variant c.92+5G>T is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Atweh G et al. A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. Blood. 1987; 70(1):147-51. PMID: 2439149.
Comment:
Converted during submission to Pathogenic.
Comment:
Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348723, 22975760, 25525159, 9163586, 2577233, 2439149, 33092414)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The molecular characterization of Beta globin gene in thalassemia patients reveals rare and a novel mutations in Pakistani population. | Yasmeen H | European journal of medical genetics | 2016 | PMID: 27263053 |
| Molecular epidemiology of β-thalassemia in Pakistan: Far reaching implications. | Ansari SH | Indian journal of human genetics | 2012 | PMID: 23162295 |
| ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of β-thalassaemia. | Shammas C | Clinical chemistry and laboratory medicine | 2010 | PMID: 20704537 |
| Profiling β-thalassaemia mutations in India at state and regional levels: implications for genetic education, screening and counselling programmes. | Sinha S | The HUGO journal | 2009 | PMID: 21119755 |
| 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 |
| Molecular genetic analyses of beta-thalassemia in South India reveals rare mutations in the beta-globin gene. | Bashyam MD | Journal of human genetics | 2004 | PMID: 15278762 |
| Real-time PCR for single-cell genotyping in sickle cell and thalassemia syndromes as a rapid, accurate, reliable, and widely applicable protocol for preimplantation genetic diagnosis. | Vrettou C | Human mutation | 2004 | PMID: 15108284 |
| Intrinsic differences between authentic and cryptic 5' splice sites. | Roca X | Nucleic acids research | 2003 | PMID: 14576320 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Levels of Hb A2 in heterozygotes and homozygotes for beta-thalassemia mutations: influence of mutations in the CACCC and ATAAA motifs of the beta-globin gene promoter. | Huisman TH | Acta haematologica | 1997 | PMID: 9401495 |
| IVS-I-1 (G-->C) in combination with -42 (C-->G) in the promoter region of the beta-globin gene in patients from Tajikistan. | Fedorov AN | Hemoglobin | 1993 | PMID: 8330981 |
| Beta-thalassemia in Turkey. | Oner R | Hemoglobin | 1990 | PMID: 2200760 |
| Mutation analysis of beta-thalassemia genes in a German family reveals a rare transversion in the first intron. | Eigel A | Human genetics | 1989 | PMID: 2703241 |
| The molecular basis of beta thalassaemia in Bulgaria. | Kalaydjieva L | Journal of medical genetics | 1989 | PMID: 2577233 |
| Hb Monroe or alpha 2 beta 230(B12)Arg----Thr, a variant associated with beta-thalassemia due to A G----C substitution adjacent to the donor splice site of the first intron. | Gonzalez-Redondo JM | Hemoglobin | 1989 | PMID: 2539344 |
| Clinical and genetic heterogeneity in black patients with homozygous beta-thalassemia from the southeastern United States. | Gonzalez-Redondo JM | Blood | 1988 | PMID: 2458145 |
| Mild and severe beta-thalassemia among homozygotes from Turkey: identification of the types by hybridization of amplified DNA with synthetic probes. | Diaz-Chico JC | Blood | 1988 | PMID: 2446680 |
| A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. | Atweh GF | Blood | 1987 | PMID: 2439149 |
| Beta thalassemia due to a novel mutation in IVS 1 sequence donor site consensus sequence creating a restriction site. | Lapoumeroulie C | Biochemical and biophysical research communications | 1986 | PMID: 3021139 |
| https://ithanet.eu/db/ithagenes?ithaID=108 | - | - | - | - |
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Text-mined citations for rs33915217 ...
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 Oct 27, 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.