rs730882215
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000566780.6(WWOX):c.606-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
ENST00000566780.6 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
WWOX | NM_016373.4 | c.606-1G>A | splice_acceptor_variant | ENST00000566780.6 | NP_057457.1 | |||
WWOX | NM_001291997.2 | c.267-1G>A | splice_acceptor_variant | NP_001278926.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WWOX | ENST00000566780.6 | c.606-1G>A | splice_acceptor_variant | 1 | NM_016373.4 | ENSP00000457230 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249520Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135376
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727244
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Developmental and epileptic encephalopathy, 28 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Pathology and Clinical Laboratory Medicine, King Fahad Medical City | - | - - |
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 14, 2024 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
Esophageal squamous cell carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PM3(strong),PM2 - |
Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This sequence change affects an acceptor splice site in intron 6 of the WWOX gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in WWOX are known to be pathogenic (PMID: 24456803, 25411445). This variant is present in population databases (rs730882215, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with clinical features of WWOX-related conditions (PMID: 27717089, 29852413). ClinVar contains an entry for this variant (Variation ID: 183303). 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. - |
Abnormal facial shape;C0557874:Global developmental delay;C4551584:Brain atrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Dec 01, 2014 | - - |
WWOX-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 20, 2022 | The WWOX c.606-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported as pathogenic for developmental and epileptic encephalopathy (Table S1, Alazami et al. 2015. PubMed ID: 25558065; Table S3, Alabdullatif et al. 2016. PubMed ID: 27717089; Kothur et al. 2018. PubMed ID: 29852413). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-78458766-G-A). Variants that disrupt the consensus splice acceptor site in WWOX are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2021 | Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in an in-frame deletion of a critical region; This variant is associated with the following publications: (PMID: 27717089, 29852413, 30361190, 25558065, 26345274, 32552793, 25411445) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at