Genetic Variant HEXB:c.-376-4189C>G (chr5-74685139-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001292004.2(HEXB):c.-376-4189C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000032 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000045 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HEXB
NM_001292004.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_001292004.2 link	c.-376-4189C>G		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0
HEXB	NM_000521.4 link	c.-122C>G		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.-122C>G		upstream_gene_variant		1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

AF:

0.0000321

AC:

AN:

31180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000807

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000445

AC:

AN:

179720

Hom.:

Cov.:

AF XY:

0.0000449

AC XY:

AN XY:

89116

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

3668

American (AMR)

AF:

0.00

AC:

AN:

5096

Ashkenazi Jewish (ASJ)

AF:

0.000362

AC:

AN:

2764

East Asian (EAS)

AF:

0.00

AC:

AN:

7634

South Asian (SAS)

AF:

0.00

AC:

AN:

9872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

498

European-Non Finnish (NFE)

AF:

0.0000436

AC:

AN:

137720

Other (OTH)

AF:

0.000122

AC:

AN:

8200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.005878), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000321

AC:

AN:

31180

Hom.:

Cov.:

AF XY:

0.0000655

AC XY:

AN XY:

15278

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

8142

American (AMR)

AF:

0.00

AC:

AN:

5414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

604

East Asian (EAS)

AF:

0.00

AC:

AN:

1462

South Asian (SAS)

AF:

0.00

AC:

AN:

964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000807

AC:

AN:

12386

Other (OTH)

AF:

0.00

AC:

AN:

410

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.0

PromoterAI

-0.27

Neutral

(source)

Splicing

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

Publications

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5-74685139-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over