rs1057519458
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000520.6(HEXA):c.425_426delTT(p.Phe142fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
HEXA
NM_000520.6 frameshift
NM_000520.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.46
Genes affected
HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-72353723-TAA-T is Pathogenic according to our data. Variant chr15-72353723-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 3932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.425_426delTT | p.Phe142fs | frameshift_variant | 4/14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.458_459delTT | p.Phe153fs | frameshift_variant | 4/14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.467_468delTT | non_coding_transcript_exon_variant | 4/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.425_426delTT | p.Phe142fs | frameshift_variant | 4/14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.412+1834_412+1835delTT | intron_variant | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460424Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726652
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tay-Sachs disease Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This variant is also known as frameshift codon 142. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3932). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 8490625). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe142*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 26, 2021 | Variant summary: HEXA c.425_426delTT (p.Phe142X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251452 control chromosomes. c.425_426delTT has been reported in the literature in individuals affected with Tay-Sachs Disease and has been subsequently cited by others (example Akli_1993). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2017 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1993 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at