chr5-74720617-G-A

Variant names:

• chr5-74720617-G-A
• rs201580118
• NM_000521.4:c.1509-26G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: -1.46

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 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 rank	MANE	Protein	UniProt
HEXB	NM_000521.4	c.1509-26G>A		intron_variant	Intron 12 of 13	ENST00000261416.12	NP_000512.2
HEXB	NM_001292004.2	c.834-26G>A		intron_variant	Intron 12 of 13		NP_001278933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXB	ENST00000261416.12	c.1509-26G>A		intron_variant	Intron 12 of 13	1	NM_000521.4	ENSP00000261416.7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32

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: 12 AN: 250940 Hom.: 0 AF XY: 0.0000663 AC XY: 9 AN XY: 135668

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: 60 AN: 1450582 Hom.: 0 Cov.: 28 AF XY: 0.0000388 AC XY: 28 AN XY: 722404

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: 1 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74288

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

Submissions by phenotype

Sandhoff disease Pathogenic:6

Jan 24, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 25, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 12, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Mar 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEXB: PM2, PM3, PP3, PP4, PS3:Supporting -

Inborn genetic diseases Pathogenic:1

Aug 09, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 15, 1990

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Pathogenic	26
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

Other links and lift over

dbSNP: rs201580118; hg19: chr5-74016442;