rs33933481
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000517.6(HBA2):c.379G>A(p.Asp127Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D127G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000517.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.379G>A | p.Asp127Asn | missense_variant | 3/3 | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.379G>A | p.Asp127Asn | missense_variant | 3/3 | 1 | NM_000517.6 | P1 | |
HBA2 | ENST00000482565.1 | n.515G>A | non_coding_transcript_exon_variant | 2/2 | 1 | ||||
ENST00000702607.1 | n.111C>T | non_coding_transcript_exon_variant | 1/1 | ||||||
HBA2 | ENST00000397806.1 | c.283G>A | p.Asp95Asn | missense_variant | 3/3 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248750Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134782
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1459020Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725574
GnomAD4 genome ? Cov.: 25
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 02, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 10, 2022 | The Hb Tarrant variant (HBA2: c.379G>A; p.Asp127Asn, also known as Asp126Asn when numbered from the mature protein, rs33933481, HbVar ID: 188) has been described in healthy individuals or individuals with mild erythrocytosis as a heterozygote and more severe erythrocytosis as a homozygote (Ibarra 1981, Ip 2016, HbVar database). The aspartate at residue 127 is located at the alpha1-alpha2 interface and forms salt bridges with Arg142 on the opposite dimer (Wajcman 2005). Variants in this region commonly lead to high oxygen affinity and reduced cooperativity (Wajcman 2005), which has been observed for the Hb Tarrant variant (Moo-Penn 1977). This variant is reported in ClinVar (Variation ID: 15662) and is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic dominant for mild erythrocytosis. References: Link to variant in HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Ibarra B et al. Heterozygosity and homozygosity for the high oxygen affinity hemoglobin Tarrant or alpha 126 (H9) Asp replaced by Asn in two Mexican families. Hemoglobin. 1981;5(4):337-48. PMID: 7019159. Ip KL et al. Hb Tarrant (a126(H9)Asp?Asn; HBA2: c.379G?>?A (or HBA1)) in a Chinese Family as a Cause of Familial Erythrocytosis. Hemoglobin. 2016 Aug;40(4):260-3. PMID: 27240426. Moo-Penn WF et al. Hemoglobin Tarrant: alpha126(H9) Asp leads to Asn. A new hemoglobin variant in the alpha1beta1 contact region showing high oxygen affinity and reduced cooperativity. Biochim Biophys Acta. 1977 Feb 22;490(2):443-51. PMID: 13856. Wajcman H et al. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. PMID: 15921161. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 09, 2020 | The variant found in at least one symptomatic individual. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. The variant has been shown to be damaging to protein function(s) relevant to disease mechanism. The variant predicted to have a damaging effect on the protein. - |
HEMOGLOBIN TARRANT Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at