rs1039151413
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_016373.4(WWOX):c.605+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_016373.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.605+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000566780.6 | |||
WWOX | NM_001291997.2 | c.266+5G>A | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.605+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_016373.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249320Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135242
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460838Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726826
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 11, 2022 | The WWOX c.605+5G>A variant occurs in a splice donor region and results in the substitution of a guanine at nucleotide position c.605+5 with an adenine. The c.605+5G>A variant is reported as an ostensibly disease-causing variant in a study describing outcomes of exome sequencing data reanalysis in a large cohort; however, specific details about the relevant case are unavailable (PMID: 31216405). Additionally, ClinVar submissions from clinical laboratories report detecting the c.605+5G>A variant in individuals with features consistent with WWOX-associated phenotypes; however, this data is currently unpublished and unavailable for review (Accession VCV000450592.4; PMID: 29165669) This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000087 in the Latino/Admixed American population (version 2.1.1). In silico prediction tools suggest that this variant may result in splice defects; however, this has not been verified experimentally. Based on the available evidence, the c.605+5G>A variant is classified as a variant of uncertain significance for developmental and epileptic encephalopathy. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 10, 2017 | The c.605+5 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.605+5 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Several in-silico splice prediction models predict that c.605+5 G>A destroys the natural donor site of intron 6 which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Developmental and epileptic encephalopathy, 28 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 10, 2022 | This sequence change falls in intron 6 of the WWOX gene. It does not directly change the encoded amino acid sequence of the WWOX protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has been observed in individual(s) with clinical features of WWOX-related conditions (Invitae). 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: 450592). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Autosomal recessive spinocerebellar ataxia 12;C4015519:Developmental and epileptic encephalopathy, 28 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 31, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at