NM_000520.6:c.459+2dupT

Variant names:

• chr15-72353688-T-TA
• rs1555473138
• NM_000520.6:c.459+2dupT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000520.6(HEXA):​c.459+2dupT variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004297647: Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID:9090529)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEXA NM_000520.6 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.33
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Tay-Sachs disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV004297647: Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 9090529).; SCV006323065: Relevant functional assessments of this variant are available in the literature (PMID: 9090529).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72353688-T-TA is Pathogenic according to our data. Variant chr15-72353688-T-TA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 558071.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.459+2dupT		splice_donor intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.492+2dupT		splice_donor intron	N/A	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.501+2dupT		splice_donor intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.459+2dupT		splice_donor intron	N/A	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.459+2dupT		splice_donor intron	N/A	ENSP00000456489.1	H3BS10
	ENSG00000260729	ENST00000379915.4	TSL:2	n.412+1870dupT		intron	N/A	ENSP00000478716.1	A0A087WUJ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Tay-Sachs disease (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.3
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: 3

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

Other links and lift over

dbSNP: rs1555473138; hg19: chr15-72646029;