rs28942071

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000268097.10(HEXA):c.1510C>T(p.Arg504Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

HEXA
ENST00000268097.10 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.43

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a helix (size 16) in uniprot entity HEXA_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000268097.10

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-72345461-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 15-72345462-G-A is Pathogenic according to our data. Variant chr15-72345462-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72345462-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HEXA	NM_000520.6 linkuse as main transcript	c.1510C>T	p.Arg504Cys	missense_variant	13/14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 linkuse as main transcript	c.1543C>T	p.Arg515Cys	missense_variant	13/14		NP_001305754.1
HEXA	NR_134869.3 linkuse as main transcript	n.1295C>T		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 linkuse as main transcript	c.1510C>T	p.Arg504Cys	missense_variant	13/14	1	NM_000520.6	ENSP00000268097	P1	P06865-1
	ENST00000570175.1 linkuse as main transcript	n.242G>A		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251454

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461832

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000223

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Apr 03, 2019	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1,PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Aug 05, 2022	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Apr 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 504 of the HEXA protein (p.Arg504Cys). This variant is present in population databases (rs28942071, gnomAD 0.006%). This missense change has been observed in individual(s) with Tay‚ÄìSachs disease (PMID: 1837283, 19091716, 25860343). ClinVar contains an entry for this variant (Variation ID: 3906). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXA function (PMID: 9694901). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 18, 2017	Variant summary: The HEXA c.1510C>T (p.Arg504Cys) variant causes a missense change involving the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain (IPR017853) (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. One functional study confirmed these predictions by finding no enzymatic activity associated with this variant (Paw_1991). The variant was found in the control population dataset of ExAC in 2/121476 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant was reported in multiple patients with Tay-Sachs disease, as a homozygous allele (Akli_1991) and in compound heterozygosity with c.805G>A (p.G269S)(pathogenic in our internal database), c.615delG (p.V206X)(not in our internal database, not in HGMD/ClinVar), and c.346+1G>A (not in our internal database, DM in HGMD)(Neudorfer_2005, Montalvo_2005, Akli_1991). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2 and 3) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with Tay-Sachs disease (PMIDs: 16088929, 15714079). (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 specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 17, 2018

The HEXA c.1510C>T; p.Arg504Cys variant (rs28942071) has been described in individuals affected with Tay-Sachs disease (TSD; Alki 1991, Montalvo 2005, Neudorfer 2005, Shapiro 2009) and GM2-gangliosidosis (Ragahavan 1985). It contains an entry in ClinVar (Variation ID: 3906) and is observed in the general population at a low overall frequency of 0.0024% (6/251454 alleles) in the Genome Aggregation database. Fibroblasts from patients harboring this variant show reduced beta-hexosaminidase A and defective GM2 ganglioside metabolism (Raghavan 1985). Further analyses of the variant protein demonstrate impaired dimerization and loss of association of alpha and beta subunits (d'Azzo 1984, Paw 1991). Additionally, other variants at this codon (c.1511G>A; p.Arg504His and c.1511G>T; p.Arg504Leu) have been described in individuals affected with TSD (Montalvo 2005, Zampieri 2012). Based on available information, the p.Arg504Cys variant is considered pathogenic. REFERENCES Alki S et al. Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments. Genomics. 1991 Sep;11(1):124-34. d'Azzo A et al. Faulty association of alpha- and beta-subunits in some forms of beta-hexosaminidase A deficiency. J Biol Chem. 1984 Sep 10;259(17):11070-4. Montalvo A et al. Molecular analysis of the HEXA gene in Italian patients with infantile and late onset Tay-Sachs disease: detection of fourteen novel alleles. Hum Mutat. 2005 Sep;26(3):282. Neudorfer O et al. Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med. 2005 Feb;7(2):119-23. Paw B et al. A third mutation at the CpG dinucleotide of codon 504 and a silent mutation at codon 506 of the HEX A gene. Am J Hum Genet. 1991 Jun;48(6):1139-46. Raghavan S et al. GM2-ganglioside metabolism in hexosaminidase A deficiency states: determination in situ using labeled GM2 added to fibroblast cultures. Am J Hum Genet. 1985 Nov;37(6):1071-82. Shapiro B et al. Late-onset Tay-Sachs disease presenting as a childhood stutter. J Neurol Neurosurg Psychiatry. 2009 Jan;80(1):94-5. Zampieri S et al. Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. Gene. 2012 May 15;499(2):262-5. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 03, 2019

PS3, PS4_moderate, PM2, PM3, PM5, PP1, PP4 -

Gm2-gangliosidosis, chronic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1991

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;.;T

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-7.4

D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.97

MVP

1.0

MPC

0.88

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

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