Genetic Variant ENST00000511181.5:c.-376-4189delC (chr5-74685138-GC-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000511181.5(HEXB):c.-376-4189delC variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23250 hom., cov: 0)

Exomes 𝑓: 0.56 ( 151750 hom. )

Consequence

HEXB
ENST00000511181.5 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.00

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:

ENSG00000306131 (HGNC:):

ENSG00000306131 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 5-74685138-GC-G is Benign according to our data. Variant chr5-74685138-GC-G is described in ClinVar as [Benign]. Clinvar id is 369507.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.-376-4189delC		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0
HEXB	NM_000521.4 link	c.-122delC		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.-122delC		upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

AF:

0.550

AC:

83244

AN:

151264

Hom.:

23232

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:

0.551

Gnomad FIN

AF:

0.622

Gnomad MID

AF:

0.582

Gnomad NFE

AF:

0.572

Gnomad OTH

AF:

0.552

GnomAD4 exome

AF:

0.563

AC:

530677

AN:

943042

Hom.:

151750

Cov.:

AF XY:

0.562

AC XY:

262327

AN XY:

466632

show subpopulations

African (AFR)

AF:

0.557

AC:

10268

AN:

18428

American (AMR)

AF:

0.375

AC:

4893

AN:

13048

Ashkenazi Jewish (ASJ)

AF:

0.577

AC:

8919

AN:

15464

East Asian (EAS)

AF:

0.477

AC:

13272

AN:

27838

South Asian (SAS)

AF:

0.566

AC:

29121

AN:

51448

European-Finnish (FIN)

AF:

0.623

AC:

18391

AN:

29542

Middle Eastern (MID)

AF:

0.588

AC:

1700

AN:

2890

European-Non Finnish (NFE)

AF:

0.567

AC:

421089

AN:

742828

Other (OTH)

AF:

0.554

AC:

23024

AN:

41556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

11883

23766

35650

47533

59416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.550

AC:

83297

AN:

151384

Hom.:

23250

Cov.:

AF XY:

0.549

AC XY:

40611

AN XY:

73934

show subpopulations

African (AFR)

AF:

0.558

AC:

23034

AN:

41274

American (AMR)

AF:

0.412

AC:

6285

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.577

AC:

2001

AN:

3468

East Asian (EAS)

AF:

0.461

AC:

2332

AN:

5064

South Asian (SAS)

AF:

0.552

AC:

2648

AN:

4798

European-Finnish (FIN)

AF:

0.622

AC:

6512

AN:

10472

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.572

AC:

38742

AN:

67748

Other (OTH)

AF:

0.550

AC:

1160

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1883

3766

5649

7532

9415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.275

Hom.:

693

Asia WGS

AF:

0.471

AC:

1634

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Benign:3

Aug 28, 2019

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:1

Jun 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

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.-376-4189delC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over