rs147155126

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000521.4(HEXB):c.214C>T(p.Leu72Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,611,790 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L72L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0076 ( 4 hom., cov: 30)

Exomes 𝑓: 0.010 ( 109 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.330

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005268872).

BP6

Variant 5-74685474-C-T is Benign according to our data. Variant chr5-74685474-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00763 (1160/151966) while in subpopulation NFE AF = 0.0104 (706/67936). AF 95% confidence interval is 0.00976. There are 4 homozygotes in GnomAd4. There are 554 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.214C>T	p.Leu72Phe	missense_variant	Exon 1 of 14	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.-376-3854C>T		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEXB	ENST00000261416.12 link	c.214C>T	p.Leu72Phe	missense_variant	Exon 1 of 14	1	NM_000521.4	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5 link	c.-376-3854C>T		intron_variant	Intron 1 of 13	1		ENSP00000426285.1	Q5URX0
HEXB	ENST00000513079.5 link	n.279C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2
HEXB	ENST00000515528.1 link	n.269C>T		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00764

AC:

1160

AN:

151848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00215

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.000974

Gnomad SAS

AF:

0.00945

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00817

GnomAD2 exomes

AF:

0.00776

AC:

1903

AN:

245082

AF XY:

0.00791

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00488

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.0000558

Gnomad FIN exome

AF:

0.00777

Gnomad NFE exome

AF:

0.0100

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.0103

AC:

15074

AN:

1459824

Hom.:

109

Cov.:

AF XY:

0.0102

AC XY:

7431

AN XY:

726230

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

33304

American (AMR)

AF:

0.00551

AC:

246

AN:

44616

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

326

AN:

26074

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39606

South Asian (SAS)

AF:

0.00827

AC:

712

AN:

86078

European-Finnish (FIN)

AF:

0.00903

AC:

477

AN:

52840

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0114

AC:

12647

AN:

1111230

Other (OTH)

AF:

0.00952

AC:

574

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

925

1851

2776

3702

4627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

500

1000

1500

2000

2500

<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:

0.00763

AC:

1160

AN:

151966

Hom.:

Cov.:

AF XY:

0.00746

AC XY:

554

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.00214

AC:

AN:

41494

American (AMR)

AF:

0.00674

AC:

103

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3466

East Asian (EAS)

AF:

0.00117

AC:

AN:

5120

South Asian (SAS)

AF:

0.00946

AC:

AN:

4756

European-Finnish (FIN)

AF:

0.00943

AC:

100

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

706

AN:

67936

Other (OTH)

AF:

0.00808

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

120

180

240

300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00950

Hom.:

Bravo

AF:

0.00738

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0112

AC:

ExAC

AF:

0.00745

AC:

904

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0106

EpiControl

AF:

0.00856

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

HEXB: BS1, BS2 -

Feb 17, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sandhoff disease

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 04, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

May 01, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 22, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HEXB-related disorder

Benign:1

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.018

MetaRNN

Benign

0.0053

MetaSVM

Uncertain

-0.12

PhyloP100

0.33

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.31

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.053

Vest4

0.22

MVP

0.82

MPC

0.49

ClinPred

0.039

GERP RS

-0.56

PromoterAI

0.060

Neutral

(source)

gMVP

0.76

Mutation Taster

=90/10

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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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