Genetic Variant HEXB:c.-376-4193C>T (chr5-74685135-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001292004.2(HEXB):c.-376-4193C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 1,052,904 control chromosomes in the GnomAD database, including 169,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23248 hom., cov: 31)

Exomes 𝑓: 0.57 ( 146198 hom. )

Consequence

HEXB
NM_001292004.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.274

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-74685135-C-T is Benign according to our data. Variant chr5-74685135-C-T is described in ClinVar as [Benign]. Clinvar id is 369506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2 link	c.-376-4193C>T		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0
HEXB	NM_000521.4 link	c.-126C>T		upstream_gene_variant		ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEXB	ENST00000511181.5 link	c.-376-4193C>T	intron_variant	Intron 1 of 13	1		ENSP00000426285.1	Q5URX0
HEXB	ENST00000261416.12 link	c.-126C>T	upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7	P07686
HEXB	ENST00000513079.5 link	n.-61C>T	upstream_gene_variant		2
HEXB	ENST00000515528.1 link	n.-71C>T	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.550

AC:

83239

AN:

151228

Hom.:

23230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.558

Gnomad AMI

AF:

0.459

Gnomad AMR

AF:

0.413

Gnomad ASJ

AF:

0.577

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.552

Gnomad FIN

AF:

0.622

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.572

Gnomad OTH

AF:

0.552

GnomAD4 exome

AF:

0.567

AC:

511065

AN:

901556

Hom.:

146198

Cov.:

AF XY:

0.566

AC XY:

253380

AN XY:

447706

show subpopulations

Gnomad4 AFR exome

AF:

0.559

Gnomad4 AMR exome

AF:

0.377

Gnomad4 ASJ exome

AF:

0.578

Gnomad4 EAS exome

AF:

0.478

Gnomad4 SAS exome

AF:

0.568

Gnomad4 FIN exome

AF:

0.623

Gnomad4 NFE exome

AF:

0.572

Gnomad4 OTH exome

AF:

0.557

GnomAD4 genome

AF:

0.550

AC:

83292

AN:

151348

Hom.:

23248

Cov.:

AF XY:

0.549

AC XY:

40614

AN XY:

73918

show subpopulations

Gnomad4 AFR

AF:

0.558

Gnomad4 AMR

AF:

0.412

Gnomad4 ASJ

AF:

0.577

Gnomad4 EAS

AF:

0.461

Gnomad4 SAS

AF:

0.552

Gnomad4 FIN

AF:

0.622

Gnomad4 NFE

AF:

0.572

Gnomad4 OTH

AF:

0.550

Alfa

AF:

0.363

Hom.:

693

Bravo

AF:

0.531

Asia WGS

AF:

0.470

AC:

1634

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.98

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over