rs398123443

Positions:

• chr5-74685373-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000261416.12(HEXB):​c.115del​(p.Val39TrpfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,588,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q38Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: HEXB ENST00000261416.12 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: -0.00500

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]

ACMG classification

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 5-74685373-AG-A is Pathogenic according to our data. Variant chr5-74685373-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 93194.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	c.115del	p.Val39TrpfsTer25	frameshift_variant	1/14	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.-376-3953del		intron_variant			NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.115del	p.Val39TrpfsTer25	frameshift_variant	1/14	1	NM_000521.4	ENSP00000261416	P1
HEXB	ENST00000511181.5	c.-376-3953del		intron_variant		1		ENSP00000426285
HEXB	ENST00000513079.5	n.180del		non_coding_transcript_exon_variant	1/6	2
HEXB	ENST00000515528.1	n.170del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 150934 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000245

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: 0.0000590

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000101 AC: 2 AN: 198568 Hom.: 0 AF XY: 0.00000913 AC XY: 1 AN XY: 109550

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: 0.0000239

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000577 AC: 83 AN: 1437922 Hom.: 0 Cov.: 31 AF XY: 0.0000546 AC XY: 39 AN XY: 713862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000242

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: 0.0000726

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 150934 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73684

Gnomad4 AFR AF: 0.0000245

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: 0.0000590

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 13, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Val39Trpfs*25) in the HEXB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant is present in population databases (rs398123443, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with Sandhoff disease (PMID: 22191674, 23046579, 24461908). ClinVar contains an entry for this variant (Variation ID: 93194). 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	Jan 08, 2019	Variant summary: HEXB c.115delG (p.Val39TrpfsX25) 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. The variant allele was found at a frequency of 1e-05 in 193790 control chromosomes (gnomAD). c.115delG has been reported in the literature in multiple individuals affected with Sandhoff Disease (Fitterer_2012, Gaignard_2013). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2019	The c.115delG variant in the HEXB gene has been reported previously in the homozygous state in an individual with Sandoff disease (Fitterer et al., 2012). The c.115delG variant causes a frameshift starting with codon Valine 39, changes this amino acid to a Tryptophan residue, and creates a premature Stop codon at position 25 of the new reading frame, denoted p.Val39TrpfsX25. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.115delG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.115delG as apathogenic variant. -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 10, 2023	PP4, PM2, PM3, PVS1 -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs398123443; hg19: chr5-73981198;