rs121907965

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000520.6(HEXA):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-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: 32)

Consequence

HEXA
NM_000520.6 initiator_codon

Scores

6
3
7

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.42
Variant links:
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
Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 576 CDS bases. Genomic position: 72351229. Lost 0.362 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-72375972-T-A is Pathogenic according to our data. Variant chr15-72375972-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 496858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72375972-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEXANM_000520.6 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 14 ENST00000268097.10 NP_000511.2 P06865-1A0A0S2Z3W3
HEXANM_001318825.2 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 14 NP_001305754.1 P06865H3BP20B4DVA7
HEXANR_134869.3 linkn.43A>T non_coding_transcript_exon_variant Exon 1 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEXAENST00000268097.10 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 14 1 NM_000520.6 ENSP00000268097.6 P06865-1
ENSG00000260729ENST00000379915.4 linkn.1A>T non_coding_transcript_exon_variant Exon 1 of 16 2 ENSP00000478716.1 A0A087WUJ7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tay-Sachs disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 12, 2024This sequence change affects the initiator methionine of the HEXA mRNA. The next in-frame methionine is located at codon 193. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1532289, 21796138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 496858). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 02, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.49
CADD
Benign
20
DANN
Benign
0.90
DEOGEN2
Benign
0.36
T;.;T;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.037
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D;D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Uncertain
0.39
D
PROVEAN
Benign
-0.17
N;N;N;.
REVEL
Uncertain
0.63
Sift
Pathogenic
0.0
D;D;D;.
Sift4G
Benign
0.53
T;T;T;D
Polyphen
0.055
B;.;.;.
Vest4
0.85
MutPred
1.0
Loss of MoRF binding (P = 0.0663);Loss of MoRF binding (P = 0.0663);Loss of MoRF binding (P = 0.0663);Loss of MoRF binding (P = 0.0663);
MVP
0.97
ClinPred
1.0
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.96
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121907965; hg19: chr15-72668313; API