ENST00000511181.5:c.-376-4242G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000511181.5(HEXB):c.-376-4242G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 657,114 control chromosomes in the GnomAD database, including 421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 330 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 91 hom. )

Consequence

HEXB
ENST00000511181.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.03

Publications

2 publications found

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 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

HEXB links:

ENSG00000306131 (HGNC:):

ENSG00000306131 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 5-74685086-G-A is Benign according to our data. Variant chr5-74685086-G-A is described in ClinVar as [Benign]. Clinvar id is 1275326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2 link	c.-376-4242G>A		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0
HEXB	NM_000521.4 link	c.-175G>A		upstream_gene_variant		ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 link	c.-175G>A		upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

AF:

0.0361

AC:

5481

AN:

151822

Hom.:

327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000383

Gnomad OTH

AF:

0.0217

GnomAD4 exome

AF:

0.00359

AC:

1816

AN:

505174

Hom.:

AF XY:

0.00308

AC XY:

809

AN XY:

262720

show subpopulations

African (AFR)

AF:

0.125

AC:

1238

AN:

9882

American (AMR)

AF:

0.00914

AC:

104

AN:

11374

Ashkenazi Jewish (ASJ)

AF:

0.00788

AC:

AN:

12556

East Asian (EAS)

AF:

0.00

AC:

AN:

25778

South Asian (SAS)

AF:

0.000461

AC:

AN:

41254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29342

Middle Eastern (MID)

AF:

0.00488

AC:

AN:

2048

European-Non Finnish (NFE)

AF:

0.000275

AC:

AN:

345896

Other (OTH)

AF:

0.00928

AC:

251

AN:

27044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

174

260

347

434

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0362

AC:

5500

AN:

151940

Hom.:

330

Cov.:

AF XY:

0.0358

AC XY:

2656

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.126

AC:

5221

AN:

41454

American (AMR)

AF:

0.0117

AC:

179

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5142

South Asian (SAS)

AF:

0.000416

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000383

AC:

AN:

67928

Other (OTH)

AF:

0.0214

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

244

487

731

974

1218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0233

Hom.:

Bravo

AF:

0.0409

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sandhoff disease

Benign:1

Sep 09, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.9

(source)

DANN

Benign

0.66

PhyloP100

1.0

PromoterAI

-0.097

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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ENST00000511181.5:c.-376-4242G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over