15-72346551-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000520.6(HEXA):c.1306A>G(p.Ile436Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.978 in 1,613,876 control chromosomes in the GnomAD database, including 778,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I436L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.89 ( 62308 hom., cov: 31)

Exomes 𝑓: 0.99 ( 715886 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -0.152

Publications

50 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2768097E-6).

BP6

Variant 15-72346551-T-C is Benign according to our data. Variant chr15-72346551-T-C is described in ClinVar as Benign. ClinVar VariationId is 93189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
HEXA	NM_000520.6 link	c.1306A>G	p.Ile436Val	missense_variant	Exon 11 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2 link	c.1339A>G	p.Ile447Val	missense_variant	Exon 11 of 14		NP_001305754.1
HEXA	NR_134869.3 link	n.1116-226A>G		intron_variant	Intron 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.1306A>G	p.Ile436Val	missense_variant	Exon 11 of 14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4 link	n.413-226A>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes

AF:

0.889

AC:

135134

AN:

152046

Hom.:

62290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.613

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.962

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

0.997

Gnomad MID

AF:

0.978

Gnomad NFE

AF:

0.998

Gnomad OTH

AF:

0.919

GnomAD2 exomes

AF:

0.970

AC:

243905

AN:

251366

AF XY:

0.979

show subpopulations

Gnomad AFR exome

AF:

0.604

Gnomad AMR exome

AF:

0.981

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.998

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.987

GnomAD4 exome

AF:

0.988

AC:

1443888

AN:

1461712

Hom.:

715886

Cov.:

AF XY:

0.989

AC XY:

719363

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.599

AC:

20047

AN:

33464

American (AMR)

AF:

0.979

AC:

43765

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26129

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39693

AN:

39698

South Asian (SAS)

AF:

0.998

AC:

86080

AN:

86250

European-Finnish (FIN)

AF:

0.998

AC:

53313

AN:

53420

Middle Eastern (MID)

AF:

0.970

AC:

5550

AN:

5722

European-Non Finnish (NFE)

AF:

0.999

AC:

1110466

AN:

1111914

Other (OTH)

AF:

0.975

AC:

58845

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

791

1582

2374

3165

3956

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21628

43256

64884

86512

108140

<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:

0.889

AC:

135203

AN:

152164

Hom.:

62308

Cov.:

AF XY:

0.892

AC XY:

66352

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.613

AC:

25398

AN:

41446

American (AMR)

AF:

0.962

AC:

14715

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3471

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5159

AN:

5162

South Asian (SAS)

AF:

0.998

AC:

4816

AN:

4826

European-Finnish (FIN)

AF:

0.997

AC:

10588

AN:

10618

Middle Eastern (MID)

AF:

0.976

AC:

287

AN:

294

European-Non Finnish (NFE)

AF:

0.998

AC:

67912

AN:

68020

Other (OTH)

AF:

0.920

AC:

1945

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

533

1067

1600

2134

2667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<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:

0.959

Hom.:

149220

Bravo

AF:

0.872

TwinsUK

AF:

0.998

AC:

3702

ALSPAC

AF:

0.999

AC:

3849

ESP6500AA

AF:

0.620

AC:

2726

ESP6500EA

AF:

0.998

AC:

8577

ExAC

AF:

0.964

AC:

117031

Asia WGS

AF:

0.976

AC:

3394

AN:

3478

EpiCase

AF:

0.997

EpiControl

AF:

0.997

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Tay-Sachs disease

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

2.5

(source)

DANN

Benign

0.76

DEOGEN2

Uncertain

0.56

D;.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.034

T;T;T

MetaRNN

Benign

0.0000013

T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.090

N;.;.

PhyloP100

-0.15

PrimateAI

Benign

0.23

PROVEAN

Benign

0.67

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.24

T;T;T

Sift4G

Benign

0.28

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.029

MPC

0.16

ClinPred

0.0049

GERP RS

-7.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.63

Mutation Taster

=96/4

polymorphism (auto)

(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