rs10805890

Variant names:

• chr5-74697056-A-G
• rs10805890
• NM_000521.4:c.619A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000521.4(HEXB):​c.619A>G​(p.Ile207Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,569,914 control chromosomes in the GnomAD database, including 20,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I207T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1616 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18635 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.39
• Publications: 55 publications found

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a chain Beta-hexosaminidase subunit beta chain B (size 189) in uniprot entity HEXB_HUMAN there are 15 pathogenic changes around while only 2 benign (88%) in NM_000521.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0040923655).
• BP6: Variant 5-74697056-A-G is Benign according to our data. Variant chr5-74697056-A-G is described in ClinVar as Benign. ClinVar VariationId is 93202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4	c.619A>G	p.Ile207Val	missense_variant	Exon 5 of 14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.-57A>G		5_prime_UTR_variant	Exon 5 of 14		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.619A>G	p.Ile207Val	missense_variant	Exon 5 of 14	1	NM_000521.4	ENSP00000261416.7
HEXB	ENST00000511181.5	c.-57A>G		5_prime_UTR_variant	Exon 5 of 14	1		ENSP00000426285.1
HEXB	ENST00000510820.1	n.338A>G		non_coding_transcript_exon_variant	Exon 3 of 4	3
HEXB	ENST00000513079.5	n.684A>G		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19447 AN: 152118 Hom.: 1609 Cov.: 32

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.0882

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.118

GnomAD2 exomes AF: 0.159 AC: 39896 AN: 250340 AF XY: 0.156

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.227

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.251

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.161

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.157 AC: 222336 AN: 1417678 Hom.: 18635 Cov.: 27 AF XY: 0.156 AC XY: 110286 AN XY: 708032

African (AFR) AF: 0.0263 AC: 868 AN: 32990

American (AMR) AF: 0.218 AC: 9729 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4488 AN: 25844

East Asian (EAS) AF: 0.234 AC: 9206 AN: 39408

South Asian (SAS) AF: 0.0904 AC: 7734 AN: 85590

European-Finnish (FIN) AF: 0.152 AC: 7915 AN: 52128

Middle Eastern (MID) AF: 0.142 AC: 809 AN: 5702

European-Non Finnish (NFE) AF: 0.161 AC: 172723 AN: 1072400

Other (OTH) AF: 0.150 AC: 8864 AN: 58950

GnomAD4 genome AF: 0.128 AC: 19462 AN: 152236 Hom.: 1616 Cov.: 32 AF XY: 0.128 AC XY: 9519 AN XY: 74436

African (AFR) AF: 0.0325 AC: 1351 AN: 41568

American (AMR) AF: 0.172 AC: 2631 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 621 AN: 3468

East Asian (EAS) AF: 0.249 AC: 1293 AN: 5184

South Asian (SAS) AF: 0.0884 AC: 427 AN: 4828

European-Finnish (FIN) AF: 0.147 AC: 1559 AN: 10596

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11121 AN: 67986

Other (OTH) AF: 0.123 AC: 259 AN: 2114

Alfa AF: 0.156 Hom.: 5561

Bravo AF: 0.128

TwinsUK AF: 0.154 AC: 571

ALSPAC AF: 0.175 AC: 676

ESP6500AA AF: 0.0363 AC: 160

ESP6500EA AF: 0.174 AC: 1498

ExAC AF: 0.151 AC: 18328

Asia WGS AF: 0.158 AC: 549 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.165

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:4

Mar 06, 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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

not specified Benign:3

Jul 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12027830, 8950198, 7633435, 24263030, 9562328, 20981092, 21150067, 21228398, 1720305, 27884173, 27021291, 31428437) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 16, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

HEXB POLYMORPHISM Benign:1

Nov 15, 1996

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	0.13
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	0.016
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.86	D
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.34
Sift	Benign	0.23	T
Sift4G	Benign	0.35	T
Vest4		0.077
MPC		0.23
ClinPred		0.012	T
GERP RS		4.8
gMVP		0.61
Mutation Taster		=289/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10805890; hg19: chr5-73992881; COSMIC: COSV54667253;