rs114661695

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000521.4(HEXB):c.1051T>C(p.Leu351Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,608,682 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0060 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 79 hom. )

Consequence

HEXB
NM_000521.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.14

Publications

3 publications found

Variant links:

Genes affected

HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

HEXB Gene-Disease associations (from GenCC):

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

HEXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.032).

BP6

Variant 5-74715659-T-C is Benign according to our data. Variant chr5-74715659-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.14 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.006 (911/151880) while in subpopulation NFE AF = 0.00911 (619/67936). AF 95% confidence interval is 0.00852. There are 7 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.1051T>C	p.Leu351Leu	synonymous_variant	Exon 8 of 14	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.376T>C	p.Leu126Leu	synonymous_variant	Exon 8 of 14		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 link	c.1051T>C	p.Leu351Leu	synonymous_variant	Exon 8 of 14	1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

AF:

0.00600

AC:

911

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00664

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.00418

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00911

Gnomad OTH

AF:

0.00958

GnomAD2 exomes

AF:

0.00673

AC:

1690

AN:

251248

AF XY:

0.00697

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00394

Gnomad ASJ exome

AF:

0.0175

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00448

Gnomad NFE exome

AF:

0.00983

Gnomad OTH exome

AF:

0.00947

GnomAD4 exome

AF:

0.00818

AC:

11919

AN:

1456802

Hom.:

Cov.:

AF XY:

0.00819

AC XY:

5939

AN XY:

725010

show subpopulations

African (AFR)

AF:

0.00186

AC:

AN:

33394

American (AMR)

AF:

0.00448

AC:

200

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

420

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00295

AC:

254

AN:

86090

European-Finnish (FIN)

AF:

0.00416

AC:

222

AN:

53412

Middle Eastern (MID)

AF:

0.0188

AC:

108

AN:

5744

European-Non Finnish (NFE)

AF:

0.00913

AC:

10113

AN:

1107544

Other (OTH)

AF:

0.00897

AC:

540

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

512

1023

1535

2046

2558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00600

AC:

911

AN:

151880

Hom.:

Cov.:

AF XY:

0.00539

AC XY:

400

AN XY:

74252

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41424

American (AMR)

AF:

0.00663

AC:

101

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00270

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00418

AC:

AN:

10534

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00911

AC:

619

AN:

67936

Other (OTH)

AF:

0.00948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

131

175

219

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00793

Hom.:

Bravo

AF:

0.00633

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00943

EpiControl

AF:

0.0103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:4

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:3

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HEXB: BP4, BP7, BS2 -

May 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.6

(source)

DANN

Benign

0.89

PhyloP100

2.1

PromoterAI

0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism

(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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rs114661695

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