5-74689296-C-T

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.300-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 1,585,054 control chromosomes in the GnomAD database, including 29,835 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4572 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25263 hom. )

Consequence

HEXB
NM_000521.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.373

Publications

10 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=-0.9).

BP6

Variant 5-74689296-C-T is Benign according to our data. Variant chr5-74689296-C-T is described in ClinVar as Benign. ClinVar VariationId is 256356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.300-32C>T		intron_variant	Intron 1 of 13	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.-376-32C>T		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HEXB	ENST00000261416.12 link	c.300-32C>T	intron_variant	Intron 1 of 13	1	NM_000521.4	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5 link	c.-376-32C>T	intron_variant	Intron 1 of 13	1		ENSP00000426285.1	Q5URX0
HEXB	ENST00000513079.5 link	n.365-32C>T	intron_variant	Intron 1 of 5	2
HEXB	ENST00000515528.1 link	n.355-32C>T	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.230

AC:

34941

AN:

152010

Hom.:

4556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.343

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.236

Gnomad ASJ

AF:

0.139

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.251

Gnomad FIN

AF:

0.174

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.177

Gnomad OTH

AF:

0.218

GnomAD2 exomes

AF:

0.203

AC:

50815

AN:

250644

AF XY:

0.200

show subpopulations

Gnomad AFR exome

AF:

0.348

Gnomad AMR exome

AF:

0.253

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.150

Gnomad FIN exome

AF:

0.168

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.195

GnomAD4 exome

AF:

0.182

AC:

261191

AN:

1432928

Hom.:

25263

Cov.:

AF XY:

0.183

AC XY:

131059

AN XY:

714568

show subpopulations

African (AFR)

AF:

0.351

AC:

11486

AN:

32730

American (AMR)

AF:

0.254

AC:

11333

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.140

AC:

3627

AN:

25964

East Asian (EAS)

AF:

0.164

AC:

6499

AN:

39558

South Asian (SAS)

AF:

0.242

AC:

20742

AN:

85638

European-Finnish (FIN)

AF:

0.166

AC:

8815

AN:

53028

Middle Eastern (MID)

AF:

0.172

AC:

976

AN:

5676

European-Non Finnish (NFE)

AF:

0.172

AC:

186572

AN:

1086198

Other (OTH)

AF:

0.187

AC:

11141

AN:

59470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

9478

18956

28433

37911

47389

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6632

13264

19896

26528

33160

<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:

0.230

AC:

34997

AN:

152126

Hom.:

4572

Cov.:

AF XY:

0.229

AC XY:

17043

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.344

AC:

14257

AN:

41482

American (AMR)

AF:

0.236

AC:

3606

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.139

AC:

481

AN:

3468

East Asian (EAS)

AF:

0.153

AC:

789

AN:

5170

South Asian (SAS)

AF:

0.251

AC:

1211

AN:

4828

European-Finnish (FIN)

AF:

0.174

AC:

1834

AN:

10562

Middle Eastern (MID)

AF:

0.171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.177

AC:

12033

AN:

68020

Other (OTH)

AF:

0.216

AC:

456

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1373

2746

4120

5493

6866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.199

Hom.:

641

Bravo

AF:

0.241

Asia WGS

AF:

0.230

AC:

799

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sandhoff disease

Benign:1

Jul 10, 2021

Genome-Nilou Lab

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

-0.90

CADD

Benign

3.1

(source)

DANN

Benign

0.33

PhyloP100

0.37

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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