rs199474830
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_001360016.2(G6PD):c.193A>G(p.Thr65Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T65N) has been classified as Uncertain significance.
Frequency
Consequence
NM_001360016.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PD | NM_001360016.2 | c.193A>G | p.Thr65Ala | missense_variant | 4/13 | ENST00000393562.10 | |
G6PD | NM_000402.4 | c.283A>G | p.Thr95Ala | missense_variant | 4/13 | ||
G6PD | NM_001042351.3 | c.193A>G | p.Thr65Ala | missense_variant | 4/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PD | ENST00000393562.10 | c.193A>G | p.Thr65Ala | missense_variant | 4/13 | 1 | NM_001360016.2 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 24
ClinVar
Submissions by phenotype
Anemia, nonspherocytic hemolytic, due to G6PD deficiency Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | curation | Dunham Lab, University of Washington | Aug 12, 2022 | Variant found in hemizygote with G6PD deficiency (PP4). Decreased activity in red blood cells of hemizygote and when expressed in E. coli (PS3). Not observed in gnomAD (PM2). Polyphen predicts as probably damaging, and further structural investigation indicates disruption of beta-alpha-beta motif and NADP binding site (PP3). Post_P 0.975 (odds of pathogenicity 350.3, Prior_P 0.1). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2018 | This sequence change replaces threonine with alanine at codon 65 of the G6PD protein (p.Thr65Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with G6PD deficiency (PMID: 25189226). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at