rs63750067
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The NM_000517.6(HBA2):c.*92A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000383 in 1,542,178 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000027 ( 0 hom., cov: 25)
Exomes 𝑓: 0.000039 ( 7 hom. )
Consequence
HBA2
NM_000517.6 3_prime_UTR
NM_000517.6 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.09
Genes affected
HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PP5
?
Variant 16-173692-A-G is Pathogenic according to our data. Variant chr16-173692-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.55). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.*92A>G | 3_prime_UTR_variant | 3/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.*92A>G | 3_prime_UTR_variant | 3/3 | 1 | NM_000517.6 | P1 | ||
HBA2 | ENST00000397806.1 | c.*92A>G | 3_prime_UTR_variant | 3/3 | 2 | ||||
ENST00000702607.1 | upstream_gene_variant | ||||||||
HBA2 | ENST00000482565.1 | downstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000268 AC: 4AN: 149158Hom.: 0 Cov.: 25
GnomAD3 genomes
?
AF:
AC:
4
AN:
149158
Hom.:
Cov.:
25
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.0000395 AC: 55AN: 1393020Hom.: 7 Cov.: 23 AF XY: 0.0000476 AC XY: 33AN XY: 693970
GnomAD4 exome
AF:
AC:
55
AN:
1393020
Hom.:
Cov.:
23
AF XY:
AC XY:
33
AN XY:
693970
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000268 AC: 4AN: 149158Hom.: 0 Cov.: 25 AF XY: 0.0000550 AC XY: 4AN XY: 72766
GnomAD4 genome
?
AF:
AC:
4
AN:
149158
Hom.:
Cov.:
25
AF XY:
AC XY:
4
AN XY:
72766
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 10, 2023 | This pathogenic variant changes the polyadenylation signal of the alpha2-globin gene from AATAAA to AATGAA and is associated with alpha-thalassemia. In the published literature, this variant has been reported in individuals with alpha thalassemia (PMID: 29627922 (2018)) and Hb H disease as homozygous and compound heterozygous with other pathogenic alpha-globin variants (PMIDs: 11410420 (2001), 7734346 (1995), 7701914 (1994), 1581238 (1992), 1281602 (1992)). Functional studies report this variant results nonfunctional and unstable mRNA (PMIDs: 1581238 (1992), 1281602 (1992)). Based on the available information, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2023 | Also known as Poly A2, poly(A), and poly A signal variant; This variant is associated with the following publications: (PMID: 34272389, 1581238, 34426522, 3337900, 29627922, 27199182, 11410420, 7734346, 31286593, 7701914, 1281602) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 30, 2023 | The PolyA (A->G) variant (HBA2: c.*92A>G, rs63750067), has been reported in multiple families with Hb H disease when homozygous or in-trans with a double gene deletion (Ma 2001, Thein 1988, Yuregir 1992, HbVar database and references therein). This variant is also reported in ClinVar (Variation ID: 15647). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The variant is located in the polyadenylation signal of HBA2, and is predicted to reduce the efficiency of polyadenylation of the globin transcript. Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database for PolyA (A->G): http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1071 Ma ES et al. Interaction between (--SEA) alpha-thalassemia deletion and uncommon non-deletional alpha-globin gene mutations in Chinese patients. Haematologica. 2001 May;86(5):539-40. PMID: 11410420. Thein SL et al. The polyadenylation site mutation in the alpha-globin gene cluster. Blood. 1988 Feb;71(2):313-9. PMID: 3337900. Yuregir G et al. Hb H disease in a Turkish family resulting from the interaction of a deletional alpha-thalassaemia-1 and a newly discovered poly A mutation. Br J Haematol. 1992; 80(4):527-32. PMID: 1581238. - |
alpha Thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 19, 2021 | - - |
beta Thalassemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.*92A>G variant in HBA2, has been reported in multiple families with Hb H disease (both in the homozygous and in the compound heterozygous state (in trans with a double gene deletion) (selected references: Ma 2001 PMID: 11410420, Thein 1988 PMID: 3337900, Yuregir 1992 PMID: 1581238, HbVar database http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=1071). This variant has also been reported in ClinVar (Variation ID: 15647). This variant has been identified in 2/68002 European and in 2/4630 South Asian chromosomes by gnomAD. The variant is located in the polyadenylation signal of HBA2, and is predicted to reduce the efficiency of polyadenylation of the globin transcript. Other variants (e.g., c*94A>G) affecting the polyadenylation signal of HBA2 have been reported in individuals with Hb H disease and have been classified as Pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hb H disease. ACMG/AMP Criteria applied: PM3 Very strong, PM2_supporting, PP3). - |
Hemoglobin H disease, nondeletional Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1992 | - - |
alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 15, 2022 | - - |
Alpha-thalassemia-2, nondeletional Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 1992 | - - |
Hemoglobin H disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at