rs771973471

chr5-74685429-TG-Tchr5-74685429-TG-TGG

Variant summary

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

The NM_000521.4(HEXB):c.171del(p.Trp57CysfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000963 in 1,453,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: HEXB NM_000521.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.59

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 5-74685429-TG-T is Pathogenic according to our data. Variant chr5-74685429-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 557707.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	c.171del	p.Trp57CysfsTer7	frameshift_variant	1/14	ENST00000261416.12
HEXB	NM_001292004.2	c.-376-3897del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.171del	p.Trp57CysfsTer7	frameshift_variant	1/14	1	NM_000521.4	P1
HEXB	ENST00000511181.5	c.-376-3897del		intron_variant		1
HEXB	ENST00000513079.5	n.236del		non_coding_transcript_exon_variant	1/6	2
HEXB	ENST00000515528.1	n.226del		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000963 AC: 14 AN: 1453052 Hom.: 0 Cov.: 31 AF XY: 0.00000969 AC XY: 7 AN XY: 722488

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2023	This sequence change creates a premature translational stop signal (p.Trp57Cysfs*7) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Sandhoff disease (PMID: 22789865). ClinVar contains an entry for this variant (Variation ID: 557707). 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	May 06, 2022	Variant summary: HEXB c.171delG (p.Trp57CysfsX7) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 224844 control chromosomes (gnomAD). c.171delG has been reported in the literature in multiple individuals affected with Sandhoff Disease (Gort_2012, Alonso-Prez_2021), including at least two homozygotes. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 11, 2018	- -

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: rs771973471; hg19: chr5-73981254;