rs121907952
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_000520.6(HEXA):c.1444G>T(p.Glu482Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 34)
Consequence
HEXA
NM_000520.6 stop_gained
NM_000520.6 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.49
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 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-72345528-C-A is Pathogenic according to our data. Variant chr15-72345528-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 918075.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1444G>T | p.Glu482Ter | stop_gained | 13/14 | ENST00000268097.10 | |
HEXA | NM_001318825.2 | c.1477G>T | p.Glu493Ter | stop_gained | 13/14 | ||
HEXA | NR_134869.3 | n.1229G>T | non_coding_transcript_exon_variant | 11/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1444G>T | p.Glu482Ter | stop_gained | 13/14 | 1 | NM_000520.6 | P1 | |
ENST00000570175.1 | n.308C>A | non_coding_transcript_exon_variant | 2/3 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Tay-Sachs disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn | - | In exon 13 of the HEXA gene, the heterozygous nonsense variant NM_000520.5:c .1444G>T;p.Glu482Ter was detected which was inherited from the patient's mother; this variant could not be detected in the father. This variant is not listed in the population-based databases. In the phenotype-related database HGMD it is listed as pathogenic (PubMed: 31388111), in the other phenotype-related databases this nonsense variant is not listed. The ACMG classification for this variant is: pathogenic (class 5: PVS1, PM2, PP5) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;D;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at