15-72344095-CT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000520.6(HEXA):c.1571del(p.Gln524ArgfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q524Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXA NM_000520.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.37

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0119 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1571del	p.Gln524ArgfsTer21	frameshift_variant	14/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1604del	p.Gln535ArgfsTer21	frameshift_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1571del	p.Gln524ArgfsTer21	frameshift_variant	14/14	1	NM_000520.6	P1
	ENST00000570175.1	n.166-1290del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tay-Sachs disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Mar 14, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555472158; hg19: chr15-72636436;