rs63749948
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000558.5(HBA1):c.332C>A(p.Ala111Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,794 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A111T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000558.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA1 | NM_000558.5 | c.332C>A | p.Ala111Asp | missense_variant | 3/3 | ENST00000320868.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA1 | ENST00000320868.9 | c.332C>A | p.Ala111Asp | missense_variant | 3/3 | 1 | NM_000558.5 | P1 | |
ENST00000702457.1 | n.177G>T | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460794Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726694
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693798:Methemoglobinemia, alpha type;C4693823:Erythrocytosis, familial, 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 22, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 15, 2021 | The Hb Petah Tikva variant (HBA1: c.332C>A; p.Ala111Asp also known as Ala110Asp when numbered from the mature protein, rs63749948) has been observed in the compound heterozygous state in multiple individuals affected with alpha thalassemia, while heterozygous individuals are described as silent carriers with no reportable symptoms (see HbVar and references therein, Gilad 2017). In addition, this variant is reported as unstable (HbVar database). This variant is also reported in ClinVar (Variation ID: 15800). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The alanine at codon 111 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.873). Based on available information, this variant is considered to be likely pathogenic. References: Link to Hb Petah Tikva https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=169&.cgifields=histD Gilad O et al. Molecular diagnosis of a-thalassemia in a multiethnic population. Eur J Haematol. 2017 Jun;98(6):553-562. - |
HEMOGLOBIN PETAH TIKVA Other:1
other, no assertion criteria provided | literature only | OMIM | Jul 20, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at