rs820878

Positions:

chr5-74685445-T-C

Variant summary

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

The NM_000521.4(HEXB):c.185T>C(p.Leu62Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,610,796 control chromosomes in the GnomAD database, including 744,515 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 71637 hom., cov: 27)

Exomes 𝑓: 0.96 ( 672878 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.769

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=7.7268027E-7).

BP6

Variant 5-74685445-T-C is Benign according to our data. Variant chr5-74685445-T-C is described in ClinVar as [Benign]. Clinvar id is 167173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74685445-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.984 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4 linkuse as main transcript	c.185T>C	p.Leu62Ser	missense_variant	1/14	ENST00000261416.12
HEXB	NM_001292004.2 linkuse as main transcript	c.-376-3883T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HEXB	ENST00000261416.12 linkuse as main transcript	c.185T>C	p.Leu62Ser	missense_variant	1/14	1	NM_000521.4	P1
HEXB	ENST00000511181.5 linkuse as main transcript	c.-376-3883T>C		intron_variant		1
HEXB	ENST00000513079.5 linkuse as main transcript	n.250T>C		non_coding_transcript_exon_variant	1/6	2
HEXB	ENST00000515528.1 linkuse as main transcript	n.240T>C		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.972

AC:

147224

AN:

151436

Hom.:

71575

Cov.:

show subpopulations

Gnomad AFR

AF:

0.993

Gnomad AMI

AF:

0.977

Gnomad AMR

AF:

0.973

Gnomad ASJ

AF:

0.971

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.967

Gnomad FIN

AF:

0.978

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.957

Gnomad OTH

AF:

0.971

GnomAD3 exomes

AF:

0.971

AC:

233065

AN:

239918

Hom.:

113243

AF XY:

0.970

AC XY:

127538

AN XY:

131504

show subpopulations

Gnomad AFR exome

AF:

0.993

Gnomad AMR exome

AF:

0.983

Gnomad ASJ exome

AF:

0.972

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.967

Gnomad FIN exome

AF:

0.980

Gnomad NFE exome

AF:

0.960

Gnomad OTH exome

AF:

0.969

GnomAD4 exome

AF:

0.960

AC:

1401122

AN:

1459242

Hom.:

672878

Cov.:

AF XY:

0.960

AC XY:

697092

AN XY:

725866

show subpopulations

Gnomad4 AFR exome

AF:

0.994

Gnomad4 AMR exome

AF:

0.981

Gnomad4 ASJ exome

AF:

0.972

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.966

Gnomad4 FIN exome

AF:

0.979

Gnomad4 NFE exome

AF:

0.955

Gnomad4 OTH exome

AF:

0.962

GnomAD4 genome

AF:

0.972

AC:

147345

AN:

151554

Hom.:

71637

Cov.:

AF XY:

0.973

AC XY:

72043

AN XY:

74014

show subpopulations

Gnomad4 AFR

AF:

0.993

Gnomad4 AMR

AF:

0.973

Gnomad4 ASJ

AF:

0.971

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.967

Gnomad4 FIN

AF:

0.978

Gnomad4 NFE

AF:

0.957

Gnomad4 OTH

AF:

0.971

Alfa

AF:

0.962

Hom.:

85253

Bravo

AF:

0.973

TwinsUK

AF:

0.956

AC:

3546

ALSPAC

AF:

0.953

AC:

3674

ESP6500AA

AF:

0.990

AC:

4347

ESP6500EA

AF:

0.959

AC:

8237

ExAC

AF:

0.970

AC:

117228

Asia WGS

AF:

0.988

AC:

3435

AN:

3478

EpiCase

AF:

0.960

EpiControl

AF:

0.962

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: High allele frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

4.1

DANN

Benign

0.70

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.00047

MetaRNN

Benign

7.7e-7

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.54

PROVEAN

Benign

2.7

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.83

Vest4

0.025

MPC

0.24

ClinPred

0.0033

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.32

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