15-72375972-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000520.6(HEXA):ā€‹c.1A>Cā€‹(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,130 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 Pathogenic (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

HEXA
NM_000520.6 initiator_codon

Scores

6
3
7

Clinical Significance

Pathogenic criteria provided, single submitter 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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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.
PS1
Another start lost variant in NM_000520.6 (HEXA) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-72375972-T-G is Pathogenic according to our data. Variant chr15-72375972-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 619221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEXANM_000520.6 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 14 ENST00000268097.10 NP_000511.2 P06865-1A0A0S2Z3W3
HEXANM_001318825.2 linkc.1A>C p.Met1? initiator_codon_variant Exon 1 of 14 NP_001305754.1 P06865H3BP20B4DVA7
HEXANR_134869.3 linkn.43A>C 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>C p.Met1? initiator_codon_variant Exon 1 of 14 1 NM_000520.6 ENSP00000268097.6 P06865-1
ENSG00000260729ENST00000379915.4 linkn.1A>C non_coding_transcript_exon_variant Exon 1 of 16 2 ENSP00000478716.1 A0A087WUJ7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249732
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135252
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000887
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461130
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726868
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Tay-Sachs disease Pathogenic:2
Oct 26, 2018
Sema4, Sema4
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 14, 2023
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 present in population databases (rs121907965, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with Tay-Sachs disease (PMID: 9153525; Invitae). 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: 619221). This variant disrupts the c.1A nucleotide in the HEXA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 1532289, 21796138). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

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
0.88
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
0.57
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
0.99
D
GERP RS
4.6
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