rs779273534

Positions:

• chr5-74720760-T-TTAAG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000521.4(HEXB):​c.1613+15_1613+18dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,587,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: HEXB NM_000521.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: -0.614

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-74720760-T-TTAAG is Pathogenic according to our data. Variant chr5-74720760-T-TTAAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555459.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.1613+15_1613+18dup		intron_variant		ENST00000261416.12
HEXB	NM_001292004.2	c.938+15_938+18dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.1613+15_1613+18dup		intron_variant		1	NM_000521.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152058 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

GnomAD4 exome AF: 0.0000780 AC: 112 AN: 1435000 Hom.: 0 Cov.: 26 AF XY: 0.0000671 AC XY: 48 AN XY: 715674

Gnomad4 AFR exome AF: 0.0000303

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: 0.0000993

Gnomad4 OTH exome AF: 0.0000504

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

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: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Sandhoff disease Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 07, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 04, 2021	Variant summary: HEXB c.1613+15_1613+18dupAAGT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic intronic 5' splice donor site, while four predict the variant has no significant impact on splicing at the canonical splice donor site located at c.1613+1-c.1613+2. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in the addition of 16 bp sequence from intron 13 consistent with the computational splice prediction (Pierson_2013). The authors also noted the presence of normal cDNA products indicating that the mRNA produced from this allele likely underwent some degree of proper splicing resulting in a small fraction of normal beta subunits as well. The variant was absent in 250692 control chromosomes. c.1613+15_1613+18dupAAGT has been reported in the literature as a compound heterozygous genotype and as a homozygous genotype respectively in at-least two individuals, one of whom was affected with Juvenile-onset motor neuron disease (compound heterozygote, Pierson_2013). The second homozygous individual was the deceased offspring of a consanguineous couple, who was reportedly affected with Sandhoff disease, although the exact clinical description was not provided (Sallevelt_2021). These data indicate that the variant may be associated with disease. The report by Pierson_2013, also noted a very small amount of wild-type beta-subunit protein (approximately 5% of normal) and a skweing of the total HEX A activity towards the HEX-A and/or HEX S isoforms. The authors speculate that the residual low amounts of mature beta subunit protein could explain the patient's later-onset phenotype as compared to the more fulminant infantile variant of Sandhoff disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping but not all the evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs779273534; hg19: chr5-74016585;