rs797044433

chr15-72345461-CG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000520.6(HEXA):c.1510del(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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.43

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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. There are 8 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/exons	MANE	UniProt
HEXA	NM_000520.6	c.1510del	p.Arg504AlafsTer5	frameshift_variant	13/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1543del	p.Arg515AlafsTer5	frameshift_variant	13/14
HEXA	NR_134869.3	n.1295del		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1510del	p.Arg504AlafsTer5	frameshift_variant	13/14	1	NM_000520.6	P1
	ENST00000570175.1	n.243del		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461832 Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5 AN XY: 727210

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.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tay-Sachs disease Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 09, 2021	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. -
Affects, no assertion criteria provided	literature only	OMIM	Dec 15, 1989	- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs797044433; hg19: chr15-72637802;