15-72375972-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000520.6(HEXA):c.1A>C(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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HEXA
NM_000520.6 initiator_codon

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.42

Publications

14 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 93 pathogenic variants. Next in-frame start position is after 193 codons. Genomic position: 72351228. Lost 0.363 part of the original CDS.

PS1

Another start lost variant in NM_000520.6 (HEXA) was described as [Pathogenic] in ClinVar

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 VariationId is 619221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HEXA	NM_000520.6 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 link	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 14		NP_001305754.1
HEXA	NR_134869.3 link	n.43A>C		non_coding_transcript_exon_variant	Exon 1 of 11
HEXA-AS1	NR_027262.1 link	n.-141T>G		upstream_gene_variant

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249732

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461130

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726868

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:2

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. -

Oct 26, 2018

Sema4, Sema4

Significance:Likely pathogenic

Review Status:no assertion criteria provided

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

(source)

DANN

Benign

0.88

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

PhyloP100

1.4

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

GERP RS

4.6

PromoterAI

-0.23

Neutral

(source)

Varity_R

0.96

gMVP

0.59

Mutation Taster

=3/197

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over