16-173253-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000517.6(HBA2):c.224A>G(p.Asp75Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D75A) has been classified as Likely benign.
Frequency
Consequence
NM_000517.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.224A>G | p.Asp75Gly | missense_variant | 2/3 | 1 | NM_000517.6 | ENSP00000251595.6 | ||
HBA2 | ENST00000484216.1 | c.191A>G | p.Asp64Gly | missense_variant | 2/2 | 1 | ENSP00000495899.1 | |||
HBA2 | ENST00000482565.1 | n.360A>G | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
HBA2 | ENST00000397806.1 | c.128A>G | p.Asp43Gly | missense_variant | 2/3 | 2 | ENSP00000380908.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 24
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2024 | The HBA2 c.224A>G; p.Asp75Gly variant (also known as Asp74Gly when numbered from the mature protein, rs281864856) is reported in a pregnant individual with mild anemia, however, it was also found in her unaffected identical twin and father (Tang 2023). Another variant at this codon in the homologous HBA1 gene (Hb Chapel Hill, HBA1: c.224A>G; p.Asp75Gly, HbVar ID: 110) has been reported in the literature as an unstable variant with slightly increased oxygen affinity, and has been found in the heterozygous state in individuals with both mild, persistent erythrocytosis and mild anemia (see link to HbVar and references therein). The HBA2 c.224A>G; p.Asp75Gly variant is reported in ClinVar (Variation ID: 811237) but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.848). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Tang B et al. Hb Chapel Hill or Alpha2 74(EF3) Asp>Gly, a mildly unstable variant found in a Chinese family. Hematology. 2023 Dec;28(1):2187154. PMID: 36939273. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at