rs121907981
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000520.6(HEXA):āc.1422G>Cā(p.Trp474Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Consequence
NM_000520.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1422G>C | p.Trp474Cys | missense_variant, splice_region_variant | 13/14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.1455G>C | p.Trp485Cys | missense_variant, splice_region_variant | 13/14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.1207G>C | splice_region_variant, non_coding_transcript_exon_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1422G>C | p.Trp474Cys | missense_variant, splice_region_variant | 13/14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.504G>C | splice_region_variant, non_coding_transcript_exon_variant | 5/16 | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251254Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135792
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461764Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2AN XY: 727172
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152252Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74386
ClinVar
Submissions by phenotype
Tay-Sachs disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 28, 2021 | Variant summary: HEXA c.1422G>C (p.Trp474Cys) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251254 control chromosomes. c.1422G>C has been reported in the literature as a compound heterozygous genotype in at-least two affected sibling individuals with Tay-Sachs Disease who have been subsequently cited by others and included in clinical trials (example, Petroulakis_1998, Neudorfer_2005, Clarke_2011). These data indicate that the variant is likely to be associated with disease. At least one publication reports variant specific experimental evidence evaluating an impact on protein function (Petroulakis_1998). The most pronounced variant effect results in <10% of normal enzyme activity measured as expressed levels of alpha-subunit activity in COS-7 cells. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 474 of the HEXA protein (p.Trp474Cys). This variant is present in population databases (rs121907981, gnomAD 0.003%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 9603435). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3941). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HEXA function (PMID: 9603435). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 11, 2019 | - - |
Gm2-gangliosidosis, subacute Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1998 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at