rs201580118

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000521.4(HEXB):c.1509-26G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000381 in 1,602,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

HEXB
NM_000521.4 intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-74720617-G-A is Pathogenic according to our data. Variant chr5-74720617-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 527971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXB	NM_000521.4 linkuse as main transcript	c.1509-26G>A		intron_variant		ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2 linkuse as main transcript	c.834-26G>A		intron_variant			NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12 linkuse as main transcript	c.1509-26G>A		intron_variant		1	NM_000521.4	ENSP00000261416	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

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

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

250940

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000414

AC:

AN:

1450582

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

722404

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000481

Gnomad4 OTH exome

AF:

0.0000833

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

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:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Sandhoff disease

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 24, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 14, 2023	This sequence change falls in intron 12 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201580118, gnomAD 0.01%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 2522450, 17015493, 22789865, 24915922; Invitae). ClinVar contains an entry for this variant (Variation ID: 527971). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 2522450). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 12, 2018	Variant summary: HEXB c.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Nakano_1989). The variant allele was found at a frequency of 4.9e-05 in 245836 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (4.9e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.1509-26G>A, has been reported in the literature in multiple individuals affected with Sandhoff Disease, homozygotes and compound heterozygotes (Delnooz_2009, Gort_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Delnooz_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 24, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 25, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2023	Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-26; This variant is associated with the following publications: (PMID: 23046579, 2522450, 24915922, 17015493, 22789865, 2147031, 2170400, 1386607, 2147027, 27021291, 20798201) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	HEXB: PM2, PM3, PP3, PP4, PS3:Supporting -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (12/250940) total alleles studied. The highest observed frequency was 0.01% (12/113452) of European (non-Finnish) alleles. This alteration has been reported in association with Sandhoff disease in homozygotes and in heterozygotes with an additional HEXB variant (Maegawa, 2006; Delnooz, 2010; Gort, 2012; Zhang 2016). Experimental evidence suggests this alteration has an impact on splicing resulting in an in-frame insertion of 24 nucleotides and 8 amino acids (Nakano, 1989). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -

Sandhoff disease, juvenile form

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 15, 1990

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Pathogenic

DANN

Benign

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.95

Position offset: 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