rs17561000

chr5-74713502-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.772-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0834 in 1,607,770 control chromosomes in the GnomAD database, including 6,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (430 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5819 hom.)
• Consequence: HEXB NM_000521.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003431
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.791

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 (BayesDel_noAF=-0.77).
• BP6: Variant 5-74713502-A-G is Benign according to our data. Variant chr5-74713502-A-G is described in ClinVar as [Benign]. Clinvar id is 93203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.093 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.772-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261416.12
HEXB	NM_001292004.2	c.97-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.772-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000521.4	P1
HEXB	ENST00000511181.5	c.97-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
HEXB	ENST00000504459.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0672 AC: 10228 AN: 152128 Hom.: 430 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0504

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.0750

GnomAD3 exomes AF: 0.0722 AC: 18139 AN: 251386 Hom.: 910 AF XY: 0.0745 AC XY: 10119 AN XY: 135864

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0399

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0503

Gnomad FIN exome AF: 0.117

Gnomad NFE exome AF: 0.0946

Gnomad OTH exome AF: 0.0794

GnomAD4 exome AF: 0.0851 AC: 123929 AN: 1455524 Hom.: 5819 Cov.: 29 AF XY: 0.0848 AC XY: 61402 AN XY: 724472

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0409

Gnomad4 ASJ exome AF: 0.119

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0531

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0929

Gnomad4 OTH exome AF: 0.0798

GnomAD4 genome AF: 0.0672 AC: 10230 AN: 152246 Hom.: 430 Cov.: 32 AF XY: 0.0676 AC XY: 5033 AN XY: 74458

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0538

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0512

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.0950

Gnomad4 OTH AF: 0.0747

Alfa AF: 0.0881 Hom.: 1086

Bravo AF: 0.0596

Asia WGS AF: 0.0230 AC: 81 AN: 3478

EpiCase AF: 0.0991

EpiControl AF: 0.0936

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2016	Variant summary: The HEXB c.772-4A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 8848/121370 control chromosomes (502 homozygotes) at a frequency of 0.072901, which is approximately 49 times the estimated maximal expected allele frequency of a pathogenic HEXB variant (0.001479), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 13, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	9.5
Dann	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.018
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: rs17561000; hg19: chr5-74009327;