rs121907965

Variant names:

Your query was ambiguous. Multiple possible variants found:

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

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]

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

HEXA-AS1 (HGNC:25810): (HEXA antisense RNA 1)

HEXA-AS1 links:

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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 193 codons. Genomic position: 72351228. Lost 0.363 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
HEXA	NM_000520.6 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.43A>T		non_coding_transcript_exon_variant	Exon 1 of 11
HEXA-AS1	NR_027262.1 link	n.-141T>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.1A>T		non_coding_transcript_exon_variant	Exon 1 of 16	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:1

Jan 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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

Mar 02, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.36

T;.;T;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.037

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

0.39

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over