15-72345528-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000520.6(HEXA):c.1444G>A(p.Glu482Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,102 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 (★★).
Frequency
Consequence
NM_000520.6 missense
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1444G>A | p.Glu482Lys | missense_variant | Exon 13 of 14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.1477G>A | p.Glu493Lys | missense_variant | Exon 13 of 14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.1229G>A | non_coding_transcript_exon_variant | Exon 11 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1444G>A | p.Glu482Lys | missense_variant | Exon 13 of 14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.526G>A | non_coding_transcript_exon_variant | Exon 5 of 16 | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251424Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135884
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461862Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727228
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74374
ClinVar
Submissions by phenotype
Tay-Sachs disease Pathogenic:4Other:1
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 482 of the HEXA protein (p.Glu482Lys). This variant is present in population databases (rs121907952, gnomAD 0.006%). This missense change has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1301190, 2970528, 9338583, 16088929). ClinVar contains an entry for this variant (Variation ID: 3892). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1301190, 8328462, 27682588). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: HEXA c.1444G>A (p.Glu482Lys) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251424 control chromosomes. c.1444G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with Tay-Sachs Disease and in settings of multigene panel testing for neurological disorders (example, Nakano_1988, Akli_1993 overlapping Poenaru_1994, Montalvo_2005, Ganapathy_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dersh_2019). The most pronounced variant effect results in abolishment of enzymatic activity against MUGS substrate, unprocessed by lysosomal proteases and altered folding as compared to the wild-type enzyme. This study also demonstrated that this variant retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and was degraded by the proteasome, indicating clearance via ER-associated degradation (ERAD). The following publications have been ascertained in the context of this evaluation (PMID: 8490625, 27682588, 31069529, 16088929, 2970528, 7858168). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 20, catalytic domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two patients with Tay Sachs disease and has been classified as likely pathogenic and pathogenic by diagnostic laboratories (ClinVar; PMIDs: 1301190, 2970528, 16088929, 34800199, 31069529). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies on patient fibroblasts demonstrated markedly reduced enzymatic activities and in vitro analysis demonstrated this is due to altered folding and inability to be secreted (PMID: 27682588). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Inborn genetic diseases Pathogenic:1
The c.1444G>A (p.E482K) alteration is located in exon 13 (coding exon 13) of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1444, causing the glutamic acid (E) at amino acid position 482 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251424) total alleles studied. This alteration has been reported in patients with Tay-Sachs disease (Nakano, 1988; Montalvo, 2005). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Novak, 1994; Hou, 1996; Hou, 1998; Hepbildikler, 2002; Lemieux, 2006). Enzymatic activity was undetectable in both cultured patient fibroblasts and cells transiently expressing p.E482K. In addition, p.E482K was severely misfolded and degraded by the proteosome (Brown, 1993; Dersh, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -
not provided Pathogenic:1
PP3, PM2, PM3, PS3, PS4_moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at