rs11556045

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000521.4(HEXB):c.362A>G(p.Lys121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,611,362 control chromosomes in the GnomAD database, including 28,987 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3527 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25460 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.903

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050745904).

BP6

Variant 5-74689390-A-G is Benign according to our data. Variant chr5-74689390-A-G is described in ClinVar as [Benign]. Clinvar id is 3874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.362A>G	p.Lys121Arg	missense_variant	Exon 2 of 14	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.-314A>G		5_prime_UTR_variant	Exon 2 of 14		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEXB	ENST00000261416.12 link	c.362A>G	p.Lys121Arg	missense_variant	Exon 2 of 14	1	NM_000521.4	ENSP00000261416.7	P07686
HEXB	ENST00000511181 link	c.-314A>G		5_prime_UTR_variant	Exon 2 of 14	1		ENSP00000426285.1	Q5URX0
HEXB	ENST00000513079.5 link	n.427A>G		non_coding_transcript_exon_variant	Exon 2 of 6	2
HEXB	ENST00000515528.1 link	n.417A>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.208

AC:

31633

AN:

152046

Hom.:

3521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.268

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.251

Gnomad FIN

AF:

0.174

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.201

GnomAD3 exomes

AF:

0.197

AC:

49605

AN:

251398

Hom.:

5238

AF XY:

0.196

AC XY:

26626

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.269

Gnomad AMR exome

AF:

0.251

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.150

Gnomad SAS exome

AF:

0.244

Gnomad FIN exome

AF:

0.169

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.183

AC:

266797

AN:

1459198

Hom.:

25460

Cov.:

AF XY:

0.184

AC XY:

133645

AN XY:

726094

show subpopulations

Gnomad4 AFR exome

AF:

0.278

Gnomad4 AMR exome

AF:

0.250

Gnomad4 ASJ exome

AF:

0.141

Gnomad4 EAS exome

AF:

0.165

Gnomad4 SAS exome

AF:

0.243

Gnomad4 FIN exome

AF:

0.167

Gnomad4 NFE exome

AF:

0.175

Gnomad4 OTH exome

AF:

0.185

GnomAD4 genome

AF:

0.208

AC:

31673

AN:

152164

Hom.:

3527

Cov.:

AF XY:

0.208

AC XY:

15501

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.268

Gnomad4 AMR

AF:

0.228

Gnomad4 ASJ

AF:

0.139

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.251

Gnomad4 FIN

AF:

0.174

Gnomad4 NFE

AF:

0.177

Gnomad4 OTH

AF:

0.200

Alfa

AF:

0.178

Hom.:

6376

Bravo

AF:

0.216

TwinsUK

AF:

0.177

AC:

656

ALSPAC

AF:

0.183

AC:

705

ESP6500AA

AF:

0.259

AC:

1141

ESP6500EA

AF:

0.169

AC:

1452

ExAC

AF:

0.199

AC:

24137

Asia WGS

AF:

0.227

AC:

789

AN:

3478

EpiCase

AF:

0.171

EpiControl

AF:

0.177

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:5

Sep 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Dec 15, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEXB POLYMORPHISM

Benign:1

Feb 05, 1992

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.056

DANN

Benign

0.33

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0035

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.90

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.35

REVEL

Benign

0.21

Sift

Benign

0.63

Sift4G

Benign

0.61

Vest4

0.011

MPC

0.14

ClinPred

0.0013

GERP RS

-7.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over