rs121907970

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP3BP4BP6_Very_StrongBS2

The NM_000520.6(HEXA):c.739C>T(p.Arg247Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,084 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 7 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1B:6O:3

Conservation

PhyloP100: 0.906

Publications

28 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:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000520.6

PP3

Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.38934928).

BP6

Variant 15-72350584-G-A is Benign according to our data. Variant chr15-72350584-G-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 3922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HEXA	NM_000520.6 link	c.739C>T	p.Arg247Trp	missense_variant	Exon 7 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 link	c.772C>T	p.Arg258Trp	missense_variant	Exon 7 of 14		NP_001305754.1
HEXA	NR_134869.3 link	n.781C>T		non_coding_transcript_exon_variant	Exon 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.739C>T	p.Arg247Trp	missense_variant	Exon 7 of 14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4 link	n.413-4259C>T		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

270

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00345

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00154

AC:

387

AN:

251482

AF XY:

0.00163

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00315

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00289

AC:

4220

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00283

AC XY:

2057

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000524

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00364

AC:

4049

AN:

1111942

Other (OTH)

AF:

0.00172

AC:

104

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

234

468

702

936

1170

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

312

468

624

780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00177

AC:

270

AN:

152308

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41554

American (AMR)

AF:

0.000131

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00345

AC:

235

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00164

AC:

199

EpiCase

AF:

0.00327

EpiControl

AF:

0.00213

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Pathogenic:1Benign:6Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Aug 26, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 04, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31692161, 29482223, 26990548, 19858779, 22975760, 1384323, 17259242, 9169471) -

Apr 01, 2016

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HEXA: PP3, BS2 -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2024

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HEXA c.739C>T (p.Arg247Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251482 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in HEXA causing Tay-Sachs Disease phenotype (0.0014). c.739C>T is widely accepted in the field as a benign pseudodeficiency allele, with reduced HEXA enzymatic activity toward synthetic substrate(s), but not with the natural substrate. About 35% of non-Jewish individuals identified as heterozygotes by HEXA enzyme-based testing are carriers of a pseudodeficiency allele, while about 2% of Jewish individuals identified as heterozygotes by HEXA enzyme-based testing in carrier screening programs are actually heterozygous for the variant of interest (e.g. Triggs-Raine_1992). c.739C>T has been reported in the literature in individuals affected with Tay-Sachs Disease, however these reports do not provide unequivocal conclusions about association of the variant with Tay-Sachs Disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (e.g. Cao_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9169471, 1384323). ClinVar contains an entry for this variant (Variation ID: 3922). Based on the evidence outlined above, the variant was classified as benign. -

Tay-Sachs disease

Other:2

May 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- pseudodeficiency allele

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Benign (Pseudodeficiency Allele) and reported on 04-03-2023 by Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Beta-hexosaminidase a, pseudodeficiency of

Pathogenic:1

Aug 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hereditary ataxia

Benign:1

Mar 04, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;.;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

H;.;.

PhyloP100

0.91

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.8

D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.91

MVP

1.0

MPC

0.76

ClinPred

0.30

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.91

Mutation Taster

=14/86

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over