rs10805890

chr5-74697056-A-G

Variant summary

Our verdict is Benign. Variant got -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. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:10
• Conservation: PhyloP100: 1.39

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 -18 ACMG points.

• PM1: In a chain Beta-hexosaminidase subunit beta chain B (size 189) in uniprot entity HEXB_HUMAN there are 18 pathogenic changes around while only 2 benign (90%) 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 id is 93202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74697056-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
HEXB	NM_000521.4	c.619A>G	p.Ile207Val	missense_variant	5/14	ENST00000261416.12
HEXB	NM_001292004.2	c.-57A>G		5_prime_UTR_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.619A>G	p.Ile207Val	missense_variant	5/14	1	NM_000521.4	P1
HEXB	ENST00000511181.5	c.-57A>G		5_prime_UTR_variant	5/14	1
HEXB	ENST00000510820.1	n.338A>G		non_coding_transcript_exon_variant	3/4	3
HEXB	ENST00000513079.5	n.684A>G		non_coding_transcript_exon_variant	5/6	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

GnomAD3 exomes AF: 0.159 AC: 39896 AN: 250340 Hom.: 3706 AF XY: 0.156 AC XY: 21074 AN XY: 135414

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 SAS exome AF: 0.0904

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

Gnomad4 AFR exome AF: 0.0263

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.174

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.0904

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.150

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

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.249

Gnomad4 SAS AF: 0.0884

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.123

Alfa AF: 0.161 Hom.: 4310

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2015	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 12027830, 8950198, 7633435, 24263030, 9562328, 20981092, 21150067, 21228398, 1720305, 27884173, 27021291, 31428437) -

HEXB POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Nov 15, 1996

- -

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
MutationTaster	Benign	0.028	P;P
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

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

Publications

LitVar

Other links and lift over

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