Genetic Variant NM_000520.6:c.1510delC (chr15-72345461-CG-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_000520.6(HEXA):c.1510delC(p.Arg504AlafsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HEXA
NM_000520.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.43

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:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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. Fraction of 0.0503 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-72345461-CG-C is Pathogenic according to our data. Variant chr15-72345461-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 3894.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.1510delC	p.Arg504AlafsTer5	frameshift_variant	Exon 13 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1543delC	p.Arg515AlafsTer5	frameshift_variant	Exon 13 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1295delC		non_coding_transcript_exon_variant	Exon 11 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1510delC	p.Arg504AlafsTer5	frameshift_variant	Exon 13 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.592delC		non_coding_transcript_exon_variant	Exon 5 of 16	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727210

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:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:2

Dec 15, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 09, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3894). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 2531748, 16088929, 17237499). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg504Alafs*5) in the HEXA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 26 amino acid(s) of the HEXA protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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