rs764343937

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000520.6(HEXA):c.460-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,570,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 7.81

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06918239 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.3, offset of -45, new splice context is: atctccctgtgcccccatAGtaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-72353179-C-A is Pathogenic according to our data. Variant chr15-72353179-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
HEXA	NM_000520.6 linkuse as main transcript	c.460-1G>T	splice_acceptor_variant	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 linkuse as main transcript	c.493-1G>T	splice_acceptor_variant		NP_001305754.1
HEXA	NR_134869.3 linkuse as main transcript	n.502-1G>T	splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 linkuse as main transcript	c.460-1G>T		splice_acceptor_variant		1	NM_000520.6	ENSP00000268097	P1	P06865-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248284

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134136

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000423

AC:

AN:

1418680

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

708332

show subpopulations

Gnomad4 AFR exome

AF:

0.000153

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000166

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:5Other:1

Affects, no assertion criteria provided	literature only	OMIM	Jun 01, 1991	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000520.4(HEXA):c.460-1G>T is a canonical splice variant classified as likely pathogenic in the context of hexosaminidase A deficiency. c.460-1G>T has been observed in cases with relevant disease (PMID: 1827945, 31388111). Functional assessments of this variant are not available in the literature. c.460-1G>T has been observed in population frequency databases (gnomAD: AFR 0.02%). In summary, NM_000520.4(HEXA):c.460-1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2016	Variant summary: The HEXA c.460-1G>T variant involves the alteration of a conserved intronic nucleotide at the splice acceptor site of intron 4. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 3' splicing acceptor site. This variant has been found in two patients with Tay-Sachs disease in homozygous and heterozygous state, repectively. HEX A activity in these patients was extremely low or absent. This variant was also found in 3/96942 control chromosomes at a frequency of 0.0000309, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). In addition, OMIM and HGMD report this variant as pathogenic/disease variant. Taken together, this variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This sequence change affects an acceptor splice site in intron 4 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs764343937, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1827945). ClinVar contains an entry for this variant (Variation ID: 496011). 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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2023

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 31388111, 1827945) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D

GERP RS

5.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.92

Position offset: -1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over