rs761879076
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_016373.4(WWOX):c.410G>A(p.Gly137Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G137A) has been classified as Uncertain significance.
Frequency
Consequence
NM_016373.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.410G>A | p.Gly137Glu | missense_variant, splice_region_variant | 5/9 | ENST00000566780.6 | |
WWOX | NM_001291997.2 | c.71G>A | p.Gly24Glu | missense_variant, splice_region_variant | 4/8 | ||
WWOX | NM_130791.5 | c.410G>A | p.Gly137Glu | missense_variant, splice_region_variant | 5/6 | ||
WWOX | NR_120436.3 | n.649G>A | splice_region_variant, non_coding_transcript_exon_variant | 5/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.410G>A | p.Gly137Glu | missense_variant, splice_region_variant | 5/9 | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000402 AC: 10AN: 248772Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134930
GnomAD4 exome AF: 0.000139 AC: 203AN: 1461436Hom.: 0 Cov.: 31 AF XY: 0.000120 AC XY: 87AN XY: 726968
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 19, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30356099) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2017 | - - |
Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 22, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 137 of the WWOX protein (p.Gly137Glu). This variant is present in population databases (rs761879076, gnomAD 0.01%). This missense change has been observed in individual(s) with WWOX-related conditions (PMID: 30356099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 444378). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly137 amino acid residue in WWOX. Other variant(s) that disrupt this residue have been observed in individuals with WWOX-related conditions (PMID: 30919572), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Developmental and epileptic encephalopathy, 28 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Jul 08, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at