rs779273534
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
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
NM_000521.4 intron
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 1AN: 152058Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000780 AC: 112AN: 1435000Hom.: 0 Cov.: 26 AF XY: 0.0000671 AC XY: 48AN XY: 715674
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Sandhoff disease Pathogenic:1Uncertain: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
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at