rs786204721
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000520.6(HEXA):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,322 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 (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000096 ( 0 hom. )
Consequence
HEXA
NM_000520.6 start_lost
NM_000520.6 start_lost
Scores
5
5
6
Clinical Significance
Conservation
PhyloP100: 1.19
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 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000520.6 (HEXA) was described as [Pathogenic] in ClinVar as 496858
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-72375971-A-G is Pathogenic according to our data. Variant chr15-72375971-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.2T>C | p.Met1? | start_lost | 1/14 | ENST00000268097.10 | |
HEXA | NM_001318825.2 | c.2T>C | p.Met1? | start_lost | 1/14 | ||
HEXA | NR_134869.3 | n.44T>C | non_coding_transcript_exon_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.2T>C | p.Met1? | start_lost | 1/14 | 1 | NM_000520.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461218Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726912
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tay-Sachs disease Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 15, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2021 | Variant summary: HEXA c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249908 control chromosomes. c.2T>C has been reported in the literature in individuals affected with Tay-Sachs Disease (e.g. Harmon_1993, Montalvo_2005). These data indicate that the variant is associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Harmon_1993). Eight 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. In addition, other variants affecting the start codon (c.1A>C, c.1A>T, c.1A>G) have been reported to associate with Tay-Sachs disease (HGMD database). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 10, 2018 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189126). Disruption of the initiator codon has been observed in individual(s) with PMID: 16088929, 8445615, Invitae (Tay-Sachs disease). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the HEXA mRNA. The next in-frame methionine is located at codon 193. - |
Pathogenic, no assertion criteria provided | research | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Jul 18, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 6-year-old female with developmental regression, slurred speech, intellectual disability, spasticity, epilepsy, ataxia, dystonia, failure to thrive, structural brain abnormalities, nystagmus, scoliosis, constipation, swallowing difficulties. A cousin died at 15y with regression and ataxia. - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2023 | Observed in homozygous state or with another HEXA variant in patients with infantile and juvenile onset TSD (Harmon et al., 1993; Abtahi et al., 2022; Montalvo et al., 2005); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35046417, 16088929, 31130284, 34554397, 8445615) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | HEXA: PM3:Strong, PM2, PM5, PVS1:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 22, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.;T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PROVEAN
Benign
N;N;N;.
REVEL
Uncertain
Sift
Pathogenic
D;D;D;.
Sift4G
Uncertain
D;D;D;D
Polyphen
B;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0021);Gain of catalytic residue at M1 (P = 0.0021);Gain of catalytic residue at M1 (P = 0.0021);Gain of catalytic residue at M1 (P = 0.0021);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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