rs147155126

Positions:

• chr5-74685474-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000521.4(HEXB):​c.214C>T​(p.Leu72Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,611,790 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., cov: 30)
  • Exomes 𝑓: 0.010 (109 hom.)
• Consequence: HEXB NM_000521.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.330

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005268872).
• BP6: Variant 5-74685474-C-T is Benign according to our data. Variant chr5-74685474-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-74685474-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00763 (1160/151966) while in subpopulation NFE AF= 0.0104 (706/67936). AF 95% confidence interval is 0.00976. There are 4 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4	c.214C>T	p.Leu72Phe	missense_variant	1/14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.-376-3854C>T		intron_variant			NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.214C>T	p.Leu72Phe	missense_variant	1/14	1	NM_000521.4	ENSP00000261416.7
HEXB	ENST00000511181.5	c.-376-3854C>T		intron_variant		1		ENSP00000426285.1
HEXB	ENST00000513079.5	n.279C>T		non_coding_transcript_exon_variant	1/6	2
HEXB	ENST00000515528.1	n.269C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00764 AC: 1160 AN: 151848 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.000974

Gnomad SAS AF: 0.00945

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00817

GnomAD3 exomes AF: 0.00776 AC: 1903 AN: 245082 Hom.: 16 AF XY: 0.00791 AC XY: 1056 AN XY: 133488

Gnomad AFR exome AF: 0.00191

Gnomad AMR exome AF: 0.00488

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00768

Gnomad FIN exome AF: 0.00777

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.0103 AC: 15074 AN: 1459824 Hom.: 109 Cov.: 35 AF XY: 0.0102 AC XY: 7431 AN XY: 726230

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00551

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.00903

Gnomad4 NFE exome AF: 0.0114

Gnomad4 OTH exome AF: 0.00952

GnomAD4 genome AF: 0.00763 AC: 1160 AN: 151966 Hom.: 4 Cov.: 30 AF XY: 0.00746 AC XY: 554 AN XY: 74266

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.00946

Gnomad4 FIN AF: 0.00943

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00808

Alfa AF: 0.0100 Hom.: 16

Bravo AF: 0.00738

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0112 AC: 96

ExAC AF: 0.00745 AC: 904

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.00856

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	HEXB: BS1, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2019	- -

Sandhoff disease Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 04, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 22, 2016	- -

HEXB-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 15, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.018	N
MetaRNN	Benign	0.0053	T
MetaSVM	Uncertain	-0.12	T
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.053	T
Vest4		0.22
MVP		0.82
MPC		0.49
ClinPred		0.039	T
GERP RS		-0.56
gMVP		0.76

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: rs147155126; hg19: chr5-73981299; COSMIC: COSV54667854;