rs1057519463

Positions:

• chr15-72349159-GCTCATGAA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000520.6(HEXA):​c.898_905del​(p.Phe300HisfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F300F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXA NM_000520.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.21

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 Pathogenic. Variant got 11 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 15-72349159-GCTCATGAA-G is Pathogenic according to our data. Variant chr15-72349159-GCTCATGAA-G is described in ClinVar as [Pathogenic]. Clinvar id is 375359.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.898_905del	p.Phe300HisfsTer21	frameshift_variant	8/14	ENST00000268097.10
HEXA	NM_001318825.2	c.931_938del	p.Phe311HisfsTer21	frameshift_variant	8/14
HEXA	NR_134869.3	n.940_947del		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.898_905del	p.Phe300HisfsTer21	frameshift_variant	8/14	1	NM_000520.6	P1
	ENST00000570175.1	n.1578-1059_1578-1052del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Tay-Sachs disease Pathogenic:1

Pathogenic, no assertion criteria provided

research

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Sep 07, 2012

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057519463; hg19: chr15-72641500;