rs121907952

Variant names:

• chr15-72345528-C-A
• rs121907952
• NM_000520.6:c.1444G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-72345528-C-A
• chr15-72345528-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000520.6(HEXA):​c.1444G>T​(p.Glu482*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: HEXA NM_000520.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.49

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:):

ENSG00000261460 (HGNC:58304):

ACMG classification

Verdict is Pathogenic. Variant got 14 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 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-72345528-C-A is Pathogenic according to our data. Variant chr15-72345528-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 918075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1444G>T	p.Glu482*	stop_gained	Exon 13 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1477G>T	p.Glu493*	stop_gained	Exon 13 of 14		NP_001305754.1
HEXA	NR_134869.3	n.1229G>T		non_coding_transcript_exon_variant	Exon 11 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1444G>T	p.Glu482*	stop_gained	Exon 13 of 14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.526G>T		non_coding_transcript_exon_variant	Exon 5 of 16	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 23, 2024	This sequence change creates a premature translational stop signal (p.Glu482*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 31388111). ClinVar contains an entry for this variant (Variation ID: 918075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	In exon 13 of the HEXA gene, the heterozygous nonsense variant NM_000520.5:c .1444G>T;p.Glu482Ter was detected which was inherited from the patient's mother; this variant could not be detected in the father. This variant is not listed in the population-based databases. In the phenotype-related database HGMD it is listed as pathogenic (PubMed: 31388111), in the other phenotype-related databases this nonsense variant is not listed. The ACMG classification for this variant is: pathogenic (class 5: PVS1, PM2, PP5) -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 09, 2024

PP4, PM3, PVS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
Vest4		0.98
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs121907952; hg19: chr15-72637869;