rs750727201

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000520.6(HEXA):c.1393G>A(p.Asp465Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. D465E) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 7.81

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

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

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000520.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-72346261-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3719775.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 15-72346263-C-T is Pathogenic according to our data. Variant chr15-72346263-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555154.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 link	c.1393G>A	p.Asp465Asn	missense_variant	Exon 12 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1426G>A	p.Asp476Asn	missense_variant	Exon 12 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1178G>A		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1393G>A	p.Asp465Asn	missense_variant	Exon 12 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.475G>A		non_coding_transcript_exon_variant	Exon 4 of 16	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152118

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251186

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000666

AC:

AN:

1111886

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41410

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000203

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:3Uncertain:1

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 465 of the HEXA protein (p.Asp465Asn). This variant is present in population databases (rs750727201, gnomAD 0.003%). This missense change has been observed in individual(s) with Tay Sachs disease (PMID: 11317368; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 555154). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HEXA protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

May 02, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HEXA c.1393G>A (p.Asp465Asn) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 1.2e-05 in 251186 control chromosomes. c.1393G>A has been observed in individual(s) affected with Tay-Sachs Disease (Alvarez-Rodriguez_2001, internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11317368, 24583203). ClinVar contains an entry for this variant (Variation ID: 555154). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dec 06, 2017

Natera, Inc.

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 19, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

HEXA-related disorder

Pathogenic:1

Nov 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HEXA c.1393G>A variant is predicted to result in the amino acid substitution p.Asp465Asn. This variant was reported in homozygous state in an individual with Tay-Sachs disease (TSD) and parents together with four other family members, who were heterozygotes for this variant, were enzymatically defined as TSD carriers (Alvarez-Rodriguez et al. 2001. PubMed ID: 11317368). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Feb 17, 2022

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1393G>A (p.D465N) alteration is located in exon 12 (coding exon 12) of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1393, causing the aspartic acid (D) at amino acid position 465 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/251186) total alleles studied. The highest observed frequency was 0.003% (1/34554) of Latino alleles. This alteration has been reported homozygous in a patient with Tay Sachs disease. The 5 year old boy had exaggerated startle response, myoclonic jerks, progressive weakness, diminished muscle tone, and decreased eye contact. He eventually had loss of previously acquired skills, tonic seizures, hyperreflexia, increasing muscle stiffness and progressive spasticity, as well as a cherry red spot in the macula. There was no hepatomegaly or splenomegaly. His parents were enzymatically confirmed as Tay Sachs carriers and were found to be heterozygous for the c.1393G>A alteration (Alvarez-Rodríguez, 2001). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided

Pathogenic:1

Dec 04, 2018

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11317368, 24498621, 24583203) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;.;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

M;.;.

PhyloP100

7.8

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.73

Sift

Benign

0.13

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.96

D;.;.

Vest4

0.92

MutPred

0.94

Gain of MoRF binding (P = 0.0754);.;Gain of MoRF binding (P = 0.0754);

MVP

0.99

MPC

0.74

ClinPred

0.97

GERP RS

5.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.78

gMVP

0.91

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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rs750727201

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over