Genetic Variant HEXB:p.Pro11Arg (chr5-74685292-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000521.4(HEXB):c.32C>G(p.Pro11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.11

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.066851646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXB	NM_000521.4 link	c.32C>G	p.Pro11Arg	missense_variant	Exon 1 of 14	ENST00000261416.12	NP_000512.2	P07686A0A024RAJ6
HEXB	NM_001292004.2 link	c.-376-4036C>G		intron_variant	Intron 1 of 13		NP_001278933.1	P07686Q5URX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 link	c.32C>G	p.Pro11Arg	missense_variant	Exon 1 of 14	1	NM_000521.4	ENSP00000261416.7		P07686

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1400704

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31588

American (AMR)

AF:

0.00

AC:

AN:

37566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25132

East Asian (EAS)

AF:

0.00

AC:

AN:

36402

South Asian (SAS)

AF:

0.00

AC:

AN:

80408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4734

European-Non Finnish (NFE)

AF:

9.21e-7

AC:

AN:

1085882

Other (OTH)

AF:

0.00

AC:

AN:

58158

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.0098

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.33

(source)

DANN

Benign

0.68

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.0046

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.067

MetaSVM

Uncertain

-0.14

PhyloP100

-2.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.070

REVEL

Benign

0.28

Sift

Benign

0.091

Sift4G

Benign

0.11

Vest4

0.12

MutPred

0.38

Loss of glycosylation at P11 (P = 0.0135);

MVP

0.55

MPC

0.18

ClinPred

0.22

GERP RS

-8.9

PromoterAI

0.043

Neutral

(source)

gMVP

0.58

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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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5-74685292-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