rs63750367
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP5_Moderate
The NM_000517.6(HBA2):c.45G>A(p.Trp15Ter) variant causes a stop gained change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 1)
Exomes 𝑓: 0.0000052 ( 0 hom. )
Consequence
HBA2
NM_000517.6 stop_gained
NM_000517.6 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 3.88
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 55 pathogenic variants in the truncated region.
PP5
?
Variant 16-172957-G-A is Pathogenic according to our data. Variant chr16-172957-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1330495.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.45G>A | p.Trp15Ter | stop_gained | 1/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.45G>A | p.Trp15Ter | stop_gained | 1/3 | 1 | NM_000517.6 | P1 | |
HBA2 | ENST00000484216.1 | c.15G>A | p.Trp5Ter | stop_gained | 1/2 | 1 | |||
HBA2 | ENST00000482565.1 | n.64G>A | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
HBA2 | ENST00000397806.1 | c.-3G>A | splice_region_variant, 5_prime_UTR_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 1
GnomAD3 genomes
?
Cov.:
1
GnomAD4 exome AF: 0.00000519 AC: 2AN: 385588Hom.: 0 Cov.: 0 AF XY: 0.00000986 AC XY: 2AN XY: 202828
GnomAD4 exome
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GnomAD4 genome ? Cov.: 1
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 07, 2022 | The HBA2 c.45G>A; p.Trp15Ter variant (also known as Trp14Ter when numbered from the mature protein, HbVar ID: 2934), to our knowledge, is not reported in the medical literature but is reported in the HbVar database in individuals with alpha 2- thalassemia trait (see link to HbVar). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.