Genetic Variant HEXB:p.Ser49Leu (chr5-74685406-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000521.4(HEXB):c.146C>T(p.Ser49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S49S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HEXB
NM_000521.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.46

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: Genomics England PanelApp, Myriad Women’s Health, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

HEXB links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07418522).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000521.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXB	NM_000521.4	MANE Select	c.146C>T	p.Ser49Leu	missense	Exon 1 of 14	NP_000512.2	P07686
	HEXB	NM_001292004.2		c.-376-3922C>T		intron	N/A	NP_001278933.1	Q5URX0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HEXB	ENST00000261416.12	TSL:1 MANE Select	c.146C>T	p.Ser49Leu	missense	Exon 1 of 14	ENSP00000261416.7	P07686
HEXB	ENST00000511181.5	TSL:1	c.-376-3922C>T		intron	N/A	ENSP00000426285.1	Q5URX0
HEXB	ENST00000513079.5	TSL:2	n.211C>T		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445012

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32800

American (AMR)

AF:

0.00

AC:

AN:

42614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25820

East Asian (EAS)

AF:

0.00

AC:

AN:

38100

South Asian (SAS)

AF:

0.00

AC:

AN:

84770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105950

Other (OTH)

AF:

0.00

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.23

(source)

DANN

Benign

0.92

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.018

M_CAP

Benign

0.060

MetaRNN

Benign

0.074

MetaSVM

Uncertain

-0.0095

PhyloP100

-1.5

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.34

REVEL

Benign

0.17

Sift

Benign

0.30

Sift4G

Benign

0.30

Vest4

0.045

MutPred

0.30

Loss of glycosylation at S49 (P = 0.005)

MVP

0.63

MPC

0.15

ClinPred

0.073

GERP RS

-0.92

PromoterAI

-0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.28

Mutation Taster

=91/9

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over