ClinVar Genomic variation as it relates to human health
NM_000518.5(HBB):c.-50A>C
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.-50A>C
Variation ID: 36292 Accession: VCV000036292.105
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11p15.4 11: 5227071 (GRCh38) [ NCBI UCSC ] 11: 5248301 (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 Apr 4, 2013 Feb 20, 2024 Oct 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000518.5:c.-50A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
5 prime UTR NC_000011.10:g.5227071T>G NC_000011.9:g.5248301T>G NG_000007.3:g.70545A>C NG_042296.1:g.602T>G NG_046672.1:g.5006T>G NG_059281.1:g.5001A>C LRG_1232:g.5001A>C LRG_1232t1:c.-50A>C - Protein change
- Other names
- +1'A>C
- HBB, CAP, A-C
- CAP, A-C
- Canonical SPDI
- NC_000011.10:5227070:T:G
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00010
The Genome Aggregation Database (gnomAD) 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00010
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (3) |
criteria provided, single submitter
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Feb 8, 2017 | RCV000029957.14 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 28, 2023 | RCV000508619.21 | |
Pathogenic (1) |
no assertion criteria provided
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Nov 26, 1987 | RCV001838527.9 |
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
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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
(Aug 30, 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: SCV000605834.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.00085 (26/30504 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is associated … (more)
The frequency of this variant in the general population, 0.00085 (26/30504 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant is associated with mild beta (+)-thalassemia (PMID: 3683554 (1987), 22335963 (2012), 27263053 (2016), 32722952 (2020), 33491330 (2021)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Oct 28, 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: SCV000937271.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This … (more)
This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs34305195, gnomAD 0.08%). This variant has been observed in individuals with beta thalassemia (PMID: 19254853, 22335963, 27263053). This variant is also known as the "Cap+1" or "Cap site+1" variant. ClinVar contains an entry for this variant (Variation ID: 36292). Studies have shown that this variant alters HBB gene expression (PMID: 3683554). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jun 14, 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: SCV001158594.4
First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024 |
Comment:
The HBB c.-50A>C variant (rs33915217, HbVarID: 770), also known as CAP +1 (A>C), is reported in the literature in individuals affected with beta thalassemia either … (more)
The HBB c.-50A>C variant (rs33915217, HbVarID: 770), also known as CAP +1 (A>C), is reported in the literature in individuals affected with beta thalassemia either in the homozygous state or in trans to another pathogenic HBB variant (Garewal 2007, Wong 1987, HbVar database). In the heterozygous state, the c.-50A>C variant is considered “silent” and is associated with only minor hematological abnormalities, if any (Khattak 2012). This variant is reported as pathogenic/likely pathogenic by multiple laboratories in ClinVar (Variation ID: 36292), and is found in the South Asian population with an allele frequency of 0.085% (26/30,504 alleles) in the Genome Aggregation Database. This variant occurs in the 5' untranslated region at a nucleotide that is moderately conserved. Based on available information, the c.-50A>C variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Garewal G et al. The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. Eur J Haematol. 2007 Nov;79(5):417-21. PMID: 17900295. Khattak SA et al. Prevalence of various mutations in beta thalassaemia and its association with haematological parameters. J Pak Med Assoc. 2012 Jan;62(1):40-3. PMID: 22352100. Wong C et al. Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. Nature. 1987 Nov 26-Dec 2;330(6146):384-6. PMID: 3683554. (less)
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Pathogenic
(Feb 08, 2017)
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criteria provided, single submitter
Method: clinical testing
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beta Thalassemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000052612.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 11, 2022 |
Comment:
Variant summary: The HBB c.-50A>C (also known as CAP +1 A>C) variant involves the alteration of a non-conserved nucleotide, which lies in the CAP-site from … (more)
Variant summary: The HBB c.-50A>C (also known as CAP +1 A>C) variant involves the alteration of a non-conserved nucleotide, which lies in the CAP-site from where transcription starts. One in silico tool predicts a damaging outcome for this variant. This variant was found in 12/119792 control chromosomes at a frequency of 0.0001002, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). The variant was reported in numerous Beta Thalassemia patients individuals in the literature. Taken together, this variant is classified as pathogenic. (less)
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Pathogenic
(Nov 26, 1987)
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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: SCV000037005.3
First in ClinVar: Apr 04, 2013 Last updated: May 09, 2018 |
Comment on evidence:
In an Asian Indian patient with beta-plus-thalassemia (613985), Wong et al. (1986) found a cap site mutation, specifically, an A-to-C change at position 1. The … (more)
In an Asian Indian patient with beta-plus-thalassemia (613985), Wong et al. (1986) found a cap site mutation, specifically, an A-to-C change at position 1. The first nucleotide of the transcript is designated the cap site; it is usually 60-100 nucleotides 5-prime of the initiator methionine codon in the untranslated part of the transcript. The cap site is the nucleotide to which a 7-methyl-G cap is added to the mRNA transcript. The mutation reported by Wong et al. (1987) is the only cap site mutation reported to date (Kazazian, 1992). (less)
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Pathogenic
(Feb 10, 2016)
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no assertion criteria provided
Method: clinical testing
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Beta-thalassemia HBB/LCRB
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132218.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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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: SCV000537293.3
First in ClinVar: Apr 04, 2013 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 |
A rare gene variation cap +1 (A>C) (HBB: c. -50A>C) associated with codon 5 (-CT) (HBB: c.17_18delCT) mutation in Syrian family. | Murad H | Molecular genetics & genomic medicine | 2021 | PMID: 33491330 |
Novel α(0)-Thalassemia Deletion Identified in an Indian Infant with Hb H Disease. | Moore JA | Hemoglobin | 2020 | PMID: 32722952 |
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 |
An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. | Lazarin GA | Genetics in medicine : official journal of the American College of Medical Genetics | 2013 | PMID: 22975760 |
Molecular epidemiology of β-thalassemia in Pakistan: Far reaching implications. | Ansari SH | Indian journal of human genetics | 2012 | PMID: 23162295 |
Prenatal screening for β-thalassemia major reveals new and rare mutations in the Pakistani population. | Moatter T | International journal of hematology | 2012 | PMID: 22392582 |
Molecular study and genotype/phenotype correlation of β Thalassemia in Malaysia. | Sivalingam M | International journal of laboratory hematology | 2012 | PMID: 22335963 |
Regional heterogeneity of beta-thalassemia mutations in the multi ethnic Indian population. | Colah R | Blood cells, molecules & diseases | 2009 | PMID: 19254853 |
Analysis of beta globin mutations in the Indian population: presence of rare and novel mutations and region-wise heterogeneity. | Edison ES | Clinical genetics | 2008 | PMID: 18294253 |
The clinical significance of the spectrum of interactions of CAP+1 (A-->C), a silent beta-globin gene mutation, with other beta-thalassemia mutations and globin gene modifiers in north Indians. | Garewal G | European journal of haematology | 2007 | PMID: 17900295 |
Rapid detection of beta-globin gene mutations and polymorphisms by temporal temperature gradient gel electrophoresis. | Shaji RV | Clinical chemistry | 2003 | PMID: 12709369 |
Rare and unexpected mutations among Iranian beta-thalassemia patients and prenatal samples discovered by reverse-hybridization and DNA sequencing. | Najmabadi H | Haematologica | 2002 | PMID: 12368169 |
A significant beta-thalassemia heterogeneity in the United Arab Emirates. | el-Kalla S | Hemoglobin | 1997 | PMID: 9140720 |
Characterization of beta-thalassaemia mutations using direct genomic sequencing of amplified single copy DNA. | Wong C | Nature | 1987 | PMID: 3683554 |
On the origin and spread of beta-thalassemia: recurrent observation of four mutations in different ethnic groups. | Wong C | Proceedings of the National Academy of Sciences of the United States of America | 1986 | PMID: 3462712 |
Kazazian, H. H., Jr., Fearon, E. R., Waber, P. G., Lee, J. I., Antonarakis, S. E., Orkin, S. H., Vanin, E. F., Heathorn, P. S., Grosveld, F. G., Buchanan, G. R. Gamma-delta-beta thalassemia: deletion of the entire beta-globin gene cluster. (Abstract) Blood 60: 54A, 1982. | - | - | - | - |
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Text-mined citations for rs34305195 ...
HelpRecord last updated Apr 20, 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.