rs11556045

chr5-74689390-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 13/17 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.903

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]

ACMG classification

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/exons	MANE	UniProt
HEXB	NM_000521.4	c.362A>G	p.Lys121Arg	missense_variant	2/14	ENST00000261416.12
HEXB	NM_001292004.2	c.-314A>G		5_prime_UTR_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.362A>G	p.Lys121Arg	missense_variant	2/14	1	NM_000521.4	P1
HEXB	ENST00000511181.5	c.-314A>G		5_prime_UTR_variant	2/14	1
HEXB	ENST00000513079.5	n.427A>G		non_coding_transcript_exon_variant	2/6	2
HEXB	ENST00000515528.1	n.417A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31633 AN: 152046 Hom.: 3521 Cov.: 32

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

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.: 30 AF XY: 0.184 AC XY: 133645 AN XY: 726094

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.: 32 AF XY: 0.208 AC XY: 15501 AN XY: 74384

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:5

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 21, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

HEXB POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Feb 05, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.64	T
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	N
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.90	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.21
Sift	Benign	0.63	T
Sift4G	Benign	0.61	T
Vest4		0.011
MPC		0.14
ClinPred		0.0013	T
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

Other links and lift over

dbSNP: rs11556045; hg19: chr5-73985215; COSMIC: COSV54666892; COSMIC: COSV54666892;