This variant interferes with polyadenylation of the alpha-2 globin mRNA and causes the synthesis of an extended alpha-2 globin mRNA transcript (PMID: 6646217 (1983), 3024968 (1986), and HbVar (http://globin.bx.psu.edu/cgi-bin/hbvar/counter)). The c.*94A>G variant is associated with alpha-thalassemia. Homozygosity for this variant is associated with Hb H disease (PMID: 7701914 (1994), 20507641 (2010), 25370869 (2014)).
ClinVar Genomic variation as it relates to human health
NM_000517.6(HBA2):c.*94A>G
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Previous version
You are looking at a previous version of this record (VCV000375749.22). Please see
the current version.
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.
(6)
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
6
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_000517.6(HBA2):c.*94A>G
Variation ID: 375749 Accession: VCV000375749.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16p13.3 16: 173694 (GRCh38) [ NCBI UCSC ] 16: 223693 (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 2, 2017 Oct 1, 2022 Feb 11, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000517.6:c.*94A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
3 prime UTR NC_000016.10:g.173694A>G NC_000016.9:g.223693A>G NG_000006.1:g.34557A>G NG_046165.1:g.3433A>G NG_059186.1:g.2044A>G NG_059271.1:g.5848A>G LRG_1225:g.2044A>G LRG_1240:g.5848A>G LRG_1240t1:c.*94A>G - Protein change
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- Other names
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- Canonical SPDI
- NC_000016.10:173693:A: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
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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 | ||
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| 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. |
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| HBA2 | - | - |
GRCh38 GRCh37 |
4 | 346 | |
| LOC106804612 | - | - | - | GRCh38 | - | 283 |
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 (3) |
no assertion criteria provided
|
Aug 25, 2019 | RCV000417217.6 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 11, 2022 | RCV001800666.5 |
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
(Dec 01, 2020)
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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: SCV002047302.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
Comment:
This variant interferes with polyadenylation of the alpha-2 globin mRNA and causes the synthesis of an extended alpha-2 globin mRNA transcript (PMID: 6646217 (1983), 3024968 … (more)
This variant interferes with polyadenylation of the alpha-2 globin mRNA and causes the synthesis of an extended alpha-2 globin mRNA transcript (PMID: 6646217 (1983), 3024968 (1986), and HbVar (http://globin.bx.psu.edu/cgi-bin/hbvar/counter)). The c.*94A>G variant is associated with alpha-thalassemia. Homozygosity for this variant is associated with Hb H disease (PMID: 7701914 (1994), 20507641 (2010), 25370869 (2014)). (less)
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Pathogenic
(Nov 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
Accession: SCV000603877.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
The HBA2 c.*94A>G variant (rs63751269), also known as Poly A (A->G) or Hb T-Saudi, is reported in the literature in both homozygous individuals with an … (more)
The HBA2 c.*94A>G variant (rs63751269), also known as Poly A (A->G) or Hb T-Saudi, is reported in the literature in both homozygous individuals with an Hb H disease phenotype, and heterozygous carriers who were borderline microcytic and hypochromic without a significant anemia (Thein 1988, Yavarian 2005, HbVar and references therein). In addition, this variant has been observed in individuals affected with Hb H disease that also carried the pathogenic alpha -3.7 deletion (Yavarian 2005). The c.*94A>G variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant is predicted to disrupt the conserved polyadenylation signal and result in an elongated transcript. Consistent with these predictions, functional assays indicate a disruption of normal transcriptional termination and transcript polyadenylation both in cultured cells and in patient samples, resulting in reduced levels of the mature mRNA (Higgs 1983, Whitelaw 1986). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.*94A>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1070 Higgs D et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983; 306(5941):398-400. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. Whitelaw E and Proudfoot N. Alpha-thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3' end processing in the human alpha 2 globin gene. EMBO J. 1986 Nov;5(11):2915-22. Yavarian M et al. Molecular basis of Hb H disease in southwest Iran. Hemoglobin. 2005;29(1):43-50. (less)
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Pathogenic
(Feb 11, 2022)
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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: SCV002513667.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
Published functional studies demonstrate a damaging effect; specifically, the variant disrupts normal transcriptional termination and transcript polyadenylation and results in reduced levels of mature mRNA … (more)
Published functional studies demonstrate a damaging effect; specifically, the variant disrupts normal transcriptional termination and transcript polyadenylation and results in reduced levels of mature mRNA and HBA2 gene expression (Higgs et al., 1983; Whitelaw et al., 1986); Variant aliases include: T, T-Saudi , poly A1 , PA-1; This variant is associated with the following publications: (PMID: 25370869, 16103716, 20301608, 28385057, 24826794, 29032940, 22686351, 19205971, 11480787, 1281602, 6646217, 3024968, 34272389, 29627922) (less)
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Pathogenic
(Aug 25, 2019)
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no assertion criteria provided
Method: clinical testing
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alpha Thalassemia
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City
Accession: SCV001132885.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
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Pathogenic
(Dec 30, 2017)
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no assertion criteria provided
Method: clinical testing
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Alpha thalassemia
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002093855.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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alpha Thalassemia
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000503059.2
First in ClinVar: Mar 02, 2017 Last updated: Oct 01, 2022 |
|
Comment:
Comment:
The HBA2 c.*94A>G variant (rs63751269), also known as Poly A (A->G) or Hb T-Saudi, is reported in the literature in both homozygous individuals with an Hb H disease phenotype, and heterozygous carriers who were borderline microcytic and hypochromic without a significant anemia (Thein 1988, Yavarian 2005, HbVar and references therein). In addition, this variant has been observed in individuals affected with Hb H disease that also carried the pathogenic alpha -3.7 deletion (Yavarian 2005). The c.*94A>G variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant is predicted to disrupt the conserved polyadenylation signal and result in an elongated transcript. Consistent with these predictions, functional assays indicate a disruption of normal transcriptional termination and transcript polyadenylation both in cultured cells and in patient samples, resulting in reduced levels of the mature mRNA (Higgs 1983, Whitelaw 1986). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.*94A>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1070 Higgs D et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983; 306(5941):398-400. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. Whitelaw E and Proudfoot N. Alpha-thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3' end processing in the human alpha 2 globin gene. EMBO J. 1986 Nov;5(11):2915-22. Yavarian M et al. Molecular basis of Hb H disease in southwest Iran. Hemoglobin. 2005;29(1):43-50.
Comment:
Published functional studies demonstrate a damaging effect; specifically, the variant disrupts normal transcriptional termination and transcript polyadenylation and results in reduced levels of mature mRNA and HBA2 gene expression (Higgs et al., 1983; Whitelaw et al., 1986); Variant aliases include: T, T-Saudi , poly A1 , PA-1; This variant is associated with the following publications: (PMID: 25370869, 16103716, 20301608, 28385057, 24826794, 29032940, 22686351, 19205971, 11480787, 1281602, 6646217, 3024968, 34272389, 29627922)
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 variant interferes with polyadenylation of the alpha-2 globin mRNA and causes the synthesis of an extended alpha-2 globin mRNA transcript (PMID: 6646217 (1983), 3024968 (1986), and HbVar (http://globin.bx.psu.edu/cgi-bin/hbvar/counter)). The c.*94A>G variant is associated with alpha-thalassemia. Homozygosity for this variant is associated with Hb H disease (PMID: 7701914 (1994), 20507641 (2010), 25370869 (2014)).
Comment:
The HBA2 c.*94A>G variant (rs63751269), also known as Poly A (A->G) or Hb T-Saudi, is reported in the literature in both homozygous individuals with an Hb H disease phenotype, and heterozygous carriers who were borderline microcytic and hypochromic without a significant anemia (Thein 1988, Yavarian 2005, HbVar and references therein). In addition, this variant has been observed in individuals affected with Hb H disease that also carried the pathogenic alpha -3.7 deletion (Yavarian 2005). The c.*94A>G variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant is predicted to disrupt the conserved polyadenylation signal and result in an elongated transcript. Consistent with these predictions, functional assays indicate a disruption of normal transcriptional termination and transcript polyadenylation both in cultured cells and in patient samples, resulting in reduced levels of the mature mRNA (Higgs 1983, Whitelaw 1986). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for c.*94A>G: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1070 Higgs D et al. Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature. 1983; 306(5941):398-400. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. Whitelaw E and Proudfoot N. Alpha-thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3' end processing in the human alpha 2 globin gene. EMBO J. 1986 Nov;5(11):2915-22. Yavarian M et al. Molecular basis of Hb H disease in southwest Iran. Hemoglobin. 2005;29(1):43-50.
Comment:
Published functional studies demonstrate a damaging effect; specifically, the variant disrupts normal transcriptional termination and transcript polyadenylation and results in reduced levels of mature mRNA and HBA2 gene expression (Higgs et al., 1983; Whitelaw et al., 1986); Variant aliases include: T, T-Saudi , poly A1 , PA-1; This variant is associated with the following publications: (PMID: 25370869, 16103716, 20301608, 28385057, 24826794, 29032940, 22686351, 19205971, 11480787, 1281602, 6646217, 3024968, 34272389, 29627922)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Alpha-Thalassemia. | Adam MP | - | 2024 | PMID: 20301608 |
| Molecular spectrum of α-globin gene defects in the Omani population. | Hassan SM | Hemoglobin | 2014 | PMID: 25370869 |
| Alpha-thalassaemia. | Harteveld CL | Orphanet journal of rare diseases | 2010 | PMID: 20507641 |
| Molecular characterization of alpha-thalassemia determinants, beta-thalassemia alleles, and beta S haplotypes among Kuwaiti Arabs. | Adekile AD | Acta haematologica | 1994 | PMID: 7701914 |
| Alpha-thalassaemia caused by a poly(A) site mutation reveals that transcriptional termination is linked to 3' end processing in the human alpha 2 globin gene. | Whitelaw E | The EMBO journal | 1986 | PMID: 3024968 |
| Alpha-thalassaemia caused by a polyadenylation signal mutation. | Higgs DR | Nature | 1983 | PMID: 6646217 |
Text-mined citations for rs63751269 ...
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 19, 2022
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.