NM_000520.6:c.1421+1G>C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000520.6(HEXA):c.1421+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000676 in 1,612,550 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

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:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of -49, new splice context is: cttGTatgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-72346234-C-G is Pathogenic according to our data. Variant chr15-72346234-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72346234-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.1421+1G>C	splice_donor_variant, intron_variant	Intron 12 of 13	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1454+1G>C	splice_donor_variant, intron_variant	Intron 12 of 13		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1206+1G>C	splice_donor_variant, intron_variant	Intron 10 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1421+1G>C		splice_donor_variant, intron_variant	Intron 12 of 13	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.503+1G>C		splice_donor_variant, intron_variant	Intron 4 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

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:

0.000116

AC:

AN:

250594

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000726

AC:

106

AN:

1460388

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

726558

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00330

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

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:

0.000246

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:8

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 11, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 3375249, 2837213, 3362213, 9222766 and 2973464. Classification of NM_000520.4(HEXA):c.1421+1G>C is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Jan 19, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict this variant to have a major effect on splicing pattern. These predictions were confirmed by Ohno et al (1988) who showed that this variants leads to exon12 skipping. This variant has been reported in the literature in multiple affected individuals presented with classic Tay-Sachs disease. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 15% of cases in this ethnic group (Montavlo, 2005). The variant is present in the broad control population dataset of ExAC at a low frequency exclusively in European cohort (0.0165%), which does not exceed the maximum frequency for a pathogenic variant in HEXA gene (0.14%). Taking together, the variant was classified as Pathogenic. -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 12 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 (rs147324677, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 2837213, 2973464, 3362213, 3375249, 9222766). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 16088929). This variant is also known as IVS12+1G>C. ClinVar contains an entry for this variant (Variation ID: 3890). 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. -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RNA studies showed intron 12 retention. However, the authors were unable to predict whether the entire intron or only part of it was retained (PMID: 2837213). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar, PMIDs: 2837213, 23852624). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:2

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HEXA c.1421+1G>C variant (rs147324677), also known as IVS12+1G>C, is reported in the medical literature in carriers of Tay-Sachs disease as well as individuals affected with Tay-Sachs disease (Arpaia 1988, Kaufman 1997). This variant is also reported in ClinVar (Variation ID: 3890), and is found in the Ashkenazi Jewish population with an allele frequency of 0.25% (25/10032 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function Based on available information, this variant is considered to be pathogenic. References: Arpaia E et al. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85-6. Kaufman M et al. Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat. 1997;10(4):295-300. -

Apr 26, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional analysis of c.1421+1 G>C cDNA clones found that this variant results in abnormal gene splicing (Ohno et al. 1988); Kaback, M. and Desnick, R. (Updated [August 11, 2011]) Hexosaminidase A Deficiency In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997- 2015. Available at http://www.genetests.org. Accessed [Nov 2016]; Ohno et al. (1988) Biochem. Biophys. Res. Commun. 153 (1):463-9 (PMID: 2837213);; This variant is associated with the following publications: (PMID: 3362213, 25525159, 22975760, 2837213, 9222766, 2973464, 3375249, 22109873, 29795570, 16088929, 8490625, 1833974, 1387685) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.22

ClinPred

0.53

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

3.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.45

Position offset: 50

DS_DL_spliceai

0.99

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