5-74713502-A-G

Variant names:

Variant summary

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

The NM_000521.4(HEXB):c.772-4A>G variant causes a splice region, 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, intron

Scores

Splicing: ADA: 0.0003431

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.791

Publications

17 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:

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=-0.77).

BP6

Variant 5-74713502-A-G is Benign according to our data. Variant chr5-74713502-A-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.772-4A>G		splice_region_variant, intron_variant	Intron 6 of 13	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.97-4A>G		splice_region_variant, intron_variant	Intron 6 of 13		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEXB	ENST00000261416.12 link	c.772-4A>G	splice_region_variant, intron_variant	Intron 6 of 13	1	NM_000521.4	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5 link	c.97-4A>G	splice_region_variant, intron_variant	Intron 6 of 13	1		ENSP00000426285.1	Q5URX0
HEXB	ENST00000504459.5 link	n.-36A>G	upstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0672

AC:

10228

AN:

152128

Hom.:

430

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0722

AC:

18139

AN:

251386

AF XY:

0.0745

show subpopulations

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 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.:

AF XY:

0.0848

AC XY:

61402

AN XY:

724472

show subpopulations

African (AFR)

AF:

0.0136

AC:

455

AN:

33400

American (AMR)

AF:

0.0409

AC:

1827

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

3097

AN:

26074

East Asian (EAS)

AF:

0.000252

AC:

AN:

39654

South Asian (SAS)

AF:

0.0531

AC:

4572

AN:

86148

European-Finnish (FIN)

AF:

0.113

AC:

6039

AN:

53386

Middle Eastern (MID)

AF:

0.0590

AC:

340

AN:

5758

European-Non Finnish (NFE)

AF:

0.0929

AC:

102784

AN:

1106206

Other (OTH)

AF:

0.0798

AC:

4805

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

4889

9778

14667

19556

24445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3660

7320

10980

14640

18300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0672

AC:

10230

AN:

152246

Hom.:

430

Cov.:

AF XY:

0.0676

AC XY:

5033

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0166

AC:

688

AN:

41564

American (AMR)

AF:

0.0538

AC:

823

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

413

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0512

AC:

247

AN:

4820

European-Finnish (FIN)

AF:

0.125

AC:

1323

AN:

10594

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0950

AC:

6459

AN:

68012

Other (OTH)

AF:

0.0747

AC:

158

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

483

967

1450

1934

2417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0849

Hom.:

1335

Bravo

AF:

0.0596

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0991

EpiControl

AF:

0.0936

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sandhoff disease

Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 13, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.5

(source)

DANN

Benign

0.57

PhyloP100

0.79

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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