rs1002712424
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_000520.6(HEXA):āc.607T>Gā(p.Trp203Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,822 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
HEXA
NM_000520.6 missense
NM_000520.6 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 9.21
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 Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 15-72351198-A-C is Pathogenic according to our data. Variant chr15-72351198-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 556070.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.607T>G | p.Trp203Gly | missense_variant | 6/14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.640T>G | p.Trp214Gly | missense_variant | 6/14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.649T>G | non_coding_transcript_exon_variant | 6/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.607T>G | p.Trp203Gly | missense_variant | 6/14 | 1 | NM_000520.6 | ENSP00000268097 | P1 | |
ENST00000570175.1 | n.2552A>C | non_coding_transcript_exon_variant | 3/3 | 1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460602Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 726742
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74370
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tay-Sachs disease Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2022 | For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function. ClinVar contains an entry for this variant (Variation ID: 556070). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 16088929). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 203 of the HEXA protein (p.Trp203Gly). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 12, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Loss of stability (P = 0.0063);.;Loss of stability (P = 0.0063);
MVP
MPC
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