rs121907984

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000261416.12(HEXB):c.1627G>A(p.Ala543Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00048 in 1,612,544 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Synonymous variant affecting the same amino acid position (i.e. A543A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 13 hom. )

Consequence

HEXB
ENST00000261416.12 missense

Scores

Clinical Significance

Likely benign; other criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: 7.04

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000261416.12

BP4

Computational evidence support a benign effect (MetaRNN=0.061395913).

BP6

Variant 5-74721131-G-A is Benign according to our data. Variant chr5-74721131-G-A is described in ClinVar as [Likely_benign, other]. Clinvar id is 3881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74721131-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000315 (48/152216) while in subpopulation SAS AF= 0.00623 (30/4818). AF 95% confidence interval is 0.00448. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4 linkuse as main transcript	c.1627G>A	p.Ala543Thr	missense_variant	14/14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2 linkuse as main transcript	c.952G>A	p.Ala318Thr	missense_variant	14/14		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 linkuse as main transcript	c.1627G>A	p.Ala543Thr	missense_variant	14/14	1	NM_000521.4	ENSP00000261416	P1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00601

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000860

AC:

216

AN:

251138

Hom.:

AF XY:

0.00119

AC XY:

162

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00572

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000497

AC:

726

AN:

1460328

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

484

AN XY:

726546

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00609

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000122

Gnomad4 OTH exome

AF:

0.000531

GnomAD4 genome

AF:

0.000315

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000213

Hom.:

Bravo

AF:

0.000140

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000947

AC:

115

Asia WGS

AF:

0.00231

AC:

AN:

3476

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign; other

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 18, 2018	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2016	Variant summary: The HEXB c.1627G>A (p.Ala543Thr) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 115/120804 (1/1052, 1 homozygote), predominantly observed in the South Asian cohort, 92/16490 (1/179, 1 homozygote), which exceeds the estimated maximal expected allele frequency for a pathogenic HEXB variant of 1/676. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has been reported in multiple affected and healthy homozygous individuals via publications. Functional studies have shown that the variant of interest is a heat labile allele, meaning that it leads to reduction in enzyme activity and mightresult in a false non-TSD or non-SD diagnosis. Likewise, a doubly heterozygous person, for TSD and for HLB, could be misdiagnosed as a normal homozygote. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "benign," along with the reporting cautionary awareness for the heat labile aspect. Therefore, to indicate the potential for the variant to cause false negative results, a classification of "Probable Normal Variant/Likely Benign," has been assigned to this variant. -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

HEXOSAMINIDASE B, HEAT-LABILE POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

T;.;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;.;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.061

T;T;T

MetaSVM

Uncertain

0.42

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.015

D;D;D

Sift4G

Uncertain

0.046

D;D;D

Vest4

0.78

MVP

0.98

MPC

0.66

ClinPred

0.24

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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