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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

WWOX
ENST00000566780.6 splice_acceptor

Scores

4
2
1
Splicing: ADA: 0.9999
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.60
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.14859438 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5, offset of 29, new splice context is: tgtgcttgtgtgcaacgcAGcaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-78424869-G-A is Pathogenic according to our data. Variant chr16-78424869-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 183303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-78424869-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-78424869-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
WWOXNM_016373.4 linkuse as main transcriptc.606-1G>A splice_acceptor_variant ENST00000566780.6 NP_057457.1
WWOXNM_001291997.2 linkuse as main transcriptc.267-1G>A splice_acceptor_variant NP_001278926.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
WWOXENST00000566780.6 linkuse as main transcriptc.606-1G>A splice_acceptor_variant 1 NM_016373.4 ENSP00000457230 P1Q9NZC7-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249520
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135376
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461874
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 28 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingPathology and Clinical Laboratory Medicine, King Fahad Medical City-- -
Pathogenic, criteria provided, single submitterresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 14, 2024- -
Likely pathogenic, no assertion criteria providedclinical testingBioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare-- -
Esophageal squamous cell carcinoma Pathogenic:1
Pathogenic, criteria provided, single submitterresearchAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalOct 04, 2024PVS1,PM3(strong),PM2 -
Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023This 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 providedresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterDec 01, 2014- -
WWOX-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 20, 2022The 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 submitterclinical testingGeneDxDec 29, 2021Not 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
28
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.97
FATHMM_MKL
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D;D;D;D;D
GERP RS
5.3

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730882215; hg19: chr16-78458766; API