rs779328596
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000521.4(HEXB):βc.1305_1306delβ(p.Arg435SerfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 32)
Exomes π: 0.0000055 ( 0 hom. )
Consequence
HEXB
NM_000521.4 frameshift
NM_000521.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.494
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 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 5-74718856-TAG-T is Pathogenic according to our data. Variant chr5-74718856-TAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554177.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.1305_1306del | p.Arg435SerfsTer20 | frameshift_variant | 11/14 | ENST00000261416.12 | |
HEXB | NM_001292004.2 | c.630_631del | p.Arg210SerfsTer20 | frameshift_variant | 11/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXB | ENST00000261416.12 | c.1305_1306del | p.Arg435SerfsTer20 | frameshift_variant | 11/14 | 1 | NM_000521.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461796Hom.: 0 AF XY: 0.00000825 AC XY: 6AN XY: 727200
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74356
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sandhoff disease Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2020 | Variant summary: HEXB c.1305_1306delAG (p.Arg435SerfsX20) 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 was absent in 251422 control chromosomes (gnomAD). c.1305_1306delAG has been reported in the literature in individuals affected with Sandhoff Disease (e.g. McInnes_1992, Gort_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence that the variant impacts protein function, as beta-hexosaminidase activity levels were measured to be 15% that of wild-type controls in patient fibroblasts from an individual homozygous for the variant (Gort_2012). One ClinVar submitter (evaluation after 2014) cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2022 | ClinVar contains an entry for this variant (Variation ID: 554177). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.1303_1304del. This premature translational stop signal has been observed in individual(s) with clinical features Sandhoff disease (PMID: 1532910, 22789865). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg435Serfs*20) 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). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 26, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at