rs1057519458

Positions:

• chr15-72353723-TAA-T
• chr15-72353723-TAA-TA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000520.6(HEXA):​c.425_426delTT​(p.Phe142fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,424 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HEXA NM_000520.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.46

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]

ENSG00000260729 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72353723-TAA-T is Pathogenic according to our data. Variant chr15-72353723-TAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 3932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.425_426delTT	p.Phe142fs	frameshift_variant	4/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.458_459delTT	p.Phe153fs	frameshift_variant	4/14		NP_001305754.1
HEXA	NR_134869.3	n.467_468delTT		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.425_426delTT	p.Phe142fs	frameshift_variant	4/14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.412+1834_412+1835delTT		intron_variant		2		ENSP00000478716.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460424 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726652

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This variant is also known as frameshift codon 142. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 3932). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 8490625). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe142*) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2021	Variant summary: HEXA c.425_426delTT (p.Phe142X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251452 control chromosomes. c.425_426delTT has been reported in the literature in individuals affected with Tay-Sachs Disease and has been subsequently cited by others (example Akli_1993). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1057519458; hg19: chr15-72646064;