rs200812468
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_016373.4(WWOX):c.173-6T>G variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.0000285 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
WWOX
NM_016373.4 splice_region, splice_polypyrimidine_tract, intron
NM_016373.4 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9170
1
1
Clinical Significance
Conservation
PhyloP100: 3.63
Genes affected
WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.173-6T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000566780.6 | |||
WWOX | NM_001291997.2 | c.-167-6T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
WWOX | NM_130791.5 | c.173-6T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ||||
WWOX | NR_120436.3 | n.412-6T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.173-6T>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000281 AC: 7AN: 249494Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135372
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727246
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152206Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change falls in intron 2 of the WWOX gene. It does not directly change the encoded amino acid sequence of the WWOX protein. This variant is present in population databases (rs200812468, gnomAD 0.006%). This variant has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 571630). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Developmental and epileptic encephalopathy, 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign in association with WWOX-related disorders to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33916893) - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 15, 2021 | The c.173-6T>G intronic alteration consists of a T to G substitution 6 nucleotides before coding exon 3 in the WWOX gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Developmental and epileptic encephalopathy, 28 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 15, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at