16-172950-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PP3_StrongBP6
The NM_000517.6(HBA2):c.38C>A(p.Ala13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.
Frequency
Consequence
NM_000517.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.38C>A | p.Ala13Asp | missense_variant | Exon 1 of 3 | 1 | NM_000517.6 | ENSP00000251595.6 | ||
HBA2 | ENST00000484216.1 | c.5C>A | p.Ala2Asp | missense_variant | Exon 1 of 2 | 1 | ENSP00000495899.1 | |||
HBA2 | ENST00000482565.1 | n.57C>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 1 | |||||
HBA2 | ENST00000397806 | c.-10C>A | 5_prime_UTR_variant | Exon 1 of 3 | 2 | ENSP00000380908.1 |
Frequencies
GnomAD3 genomes Cov.: 1
GnomAD4 exome AF: 0.0000190 AC: 7AN: 368084Hom.: 1 Cov.: 0 AF XY: 0.0000310 AC XY: 6AN XY: 193584
GnomAD4 genome Cov.: 1
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
The Hb-J-Paris-I variant (HBA2: c.38C>A; p.Ala13Asp, also known as Ala12Asp when numbered from the mature protein, rs281864809, HbVar ID: 15) is reported in the literature in individuals with no clinical symptoms or hematological alterations, and is described as a stable hemoglobin variant (see link to HbVar and references therein, de la Fuente-Gonzalo 2019, Kimura 2015, Molchanova 1994). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 13 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.558). Based on available information, this variant is considered to be likely benign. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html de la Fuente-Gonzalo F et al. Characterization of deletional and non-deletional alpha globin variants in a large cohort from Spain between 2009 and 2014. Ann Hematol. 2019 Jul;98(7):1537-1545. PMID: 31025160. Kimura EM et al. Investigating alpha-globin structural variants: a retrospective review of 135,000 Brazilian individuals. Rev Bras Hematol Hemoter. 2015 Mar-Apr;37(2):103-8. PMID: 25818820. Molchanova TP et al. The differences in quantities of alpha 2- and alpha 1-globin gene variants in heterozygotes. Br J Haematol. 1994 Oct;88(2):300-6. PMID: 7803274. -
The HBA2 c.38C>A (p.Ala13Asp) variant has been reported in the published literature in individuals with hematological indices and clinical phenotypes within normal range (PMID: 32597250 (2020), 31025160 (2019), 30489691 (2018), 27387985 (2017), 25818820 (2015), and 119167 (1979)). In an online hemoglobin database, this variant is reported as stable (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at