rs1554034452

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000521.4(HEXB):c.146C>A(p.Ser49Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,596,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S49S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HEXB
NM_000521.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: -1.46

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-74685406-C-A is Pathogenic according to our data. Variant chr5-74685406-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4 linkuse as main transcript	c.146C>A	p.Ser49Ter	stop_gained	1/14	ENST00000261416.12
HEXB	NM_001292004.2 linkuse as main transcript	c.-376-3922C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HEXB	ENST00000261416.12 linkuse as main transcript	c.146C>A	p.Ser49Ter	stop_gained	1/14	1	NM_000521.4	P1
HEXB	ENST00000511181.5 linkuse as main transcript	c.-376-3922C>A		intron_variant		1
HEXB	ENST00000513079.5 linkuse as main transcript	n.211C>A		non_coding_transcript_exon_variant	1/6	2
HEXB	ENST00000515528.1 linkuse as main transcript	n.201C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151528

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1445012

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718016

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151528

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73988

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 26, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant has been observed in individual(s) with Sandhoff disease (PMID: 22848519). ClinVar contains an entry for this variant (Variation ID: 555683). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser49*) in the HEXB gene. It is expected to result in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2019	Variant summary: HEXB c.146C>A (p.Ser49X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.850C>T (p.Arg284X)). The variant was absent in 204176 control chromosomes (gnomAD). c.146C>A has been reported in the literature in one homozygous individual affected with Sandhoff Disease while, experimental evidence evaluating an impact on protein function demostrated a residual enzymatic activity of 1.6% compared to normal control (Zampieri_2012). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

Cadd

Uncertain

Dann

Benign

0.90

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.045

MutationTaster

Benign

1.0

A;N

Vest4

0.20

GERP RS

-0.92

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over