WWOX

WW domain containing oxidoreductase, the group of Short chain dehydrogenase/reductase superfamily

Basic information

Region (hg38): 16:78099400-79212667

Links

ENSG00000186153 ∙ NCBI:51741 ∙ OMIM:605131 ∙ HGNC:12799 ∙ Uniprot:Q9NZC7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 46,XY partial gonadal dysgenesis (Supportive), mode of inheritance: AD
• autosomal recessive spinocerebellar ataxia 12 (Supportive), mode of inheritance: AR
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• autosomal recessive spinocerebellar ataxia 12 (Moderate), mode of inheritance: AR
• developmental and epileptic encephalopathy, 28 (Moderate), mode of inheritance: AR
• developmental and epileptic encephalopathy, 28 (Strong), mode of inheritance: AR
• autosomal recessive spinocerebellar ataxia 12 (Strong), mode of inheritance: AR
• developmental and epileptic encephalopathy (Definitive), mode of inheritance: AR
• autosomal recessive spinocerebellar ataxia 12 (Strong), mode of inheritance: AR
• developmental and epileptic encephalopathy, 28 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Developmental and epileptic encephalopathy 28; Spinocerebellar ataxia, autosomal recessive 12	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	17470496; 24369382; 24456803; 25411445
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the WWOX gene.

• Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12 (14 variants)
• Developmental and epileptic encephalopathy, 28 (11 variants)
• Autosomal recessive spinocerebellar ataxia 12;Developmental and epileptic encephalopathy, 1 (10 variants)
• not provided (9 variants)
• Neurodevelopmental delay (2 variants)
• WWOX-related disorder (2 variants)
• Developmental and epileptic encephalopathy, 28;Autosomal recessive spinocerebellar ataxia 12 (1 variants)
• Neurodevelopmental disorders (1 variants)
• Autosomal recessive spinocerebellar ataxia 12;Malignant tumor of esophagus;Developmental and epileptic encephalopathy, 28 (1 variants)
• Brain atrophy;Global developmental delay;Abnormal facial shape (1 variants)
• Malignant tumor of esophagus (1 variants)
• Developmental and epileptic encephalopathy, 1 (1 variants)
• Autosomal recessive spinocerebellar ataxia 12 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WWOX gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			6	162	4	172
missense	2	4	365	49	18	438
nonsense	12	8	5	3	1	29
start loss	2					2
frameshift	11	3	6	1	1	22
inframe indel	1		4			5
splice donor/acceptor (+/-2bp)	9	9	1			19
splice region			20	29	2	51
non coding			2	136	55	193
Total	37	24	389	351	79

Highest pathogenic variant AF is 0.0000132

Variants in WWOX

This is a list of pathogenic ClinVar variants found in the WWOX region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
16-78099740-A-T		not specified	Likely benign (Dec 29, 2017)
16-78099745-G-A		not specified	Likely benign (Mar 02, 2017)
16-78099752-G-A		not specified	Likely benign (May 12, 2017)
16-78099752-G-C		not specified	Likely benign (Jul 06, 2016)
16-78099754-G-A		not specified	Likely benign (Aug 18, 2017)
16-78099756-GC-T		not specified	Likely benign (Jun 09, 2017)
16-78099774-C-T		not specified • Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12 • Autosomal recessive spinocerebellar ataxia 12 • Developmental and epileptic encephalopathy, 28	Benign (Jul 15, 2024)
16-78099775-A-AG			Uncertain significance (Nov 14, 2023)
16-78099779-A-C		Autosomal recessive spinocerebellar ataxia 12;Developmental and epileptic encephalopathy, 1	Pathogenic (May 07, 2022)
16-78099780-T-C		Autosomal recessive spinocerebellar ataxia 12;Developmental and epileptic encephalopathy, 1	Pathogenic (Nov 07, 2022)
16-78099785-G-A		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Uncertain significance (Jun 24, 2020)
16-78099785-G-T		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12 • Inborn genetic diseases	Uncertain significance (Mar 07, 2024)
16-78099786-C-T		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Uncertain significance (Apr 24, 2020)
16-78099787-G-A		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Likely benign (Jun 14, 2023)
16-78099787-G-C		not specified • Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Likely benign (Apr 23, 2021)
16-78099788-C-G		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12 • Inborn genetic diseases	Uncertain significance (Dec 05, 2022)
16-78099789-T-G		Inborn genetic diseases	Uncertain significance (Mar 04, 2024)
16-78099790-G-A		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Likely benign (Mar 20, 2021)
16-78099793-C-G		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Uncertain significance (Apr 19, 2019)
16-78099794-T-C		Developmental and epileptic encephalopathy, 28	Uncertain significance (May 07, 2019)
16-78099796-C-T		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Likely benign (Sep 07, 2022)
16-78099797-G-A		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Uncertain significance (Jul 19, 2022)
16-78099802-G-A		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12	Likely benign (Jun 27, 2022)
16-78099806-G-C		Developmental and epileptic encephalopathy, 1;Autosomal recessive spinocerebellar ataxia 12 • Inborn genetic diseases	Uncertain significance (May 23, 2023)
16-78099806-G-T			Uncertain significance (Mar 26, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WWOX	protein_coding	protein_coding	ENST00000566780	9	1113255

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.24e-15	0.00594	124748	0	53	124801	0.000212

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-4.44	435	241	1.81	0.0000154	2682
Missense in Polyphen		101	62.247	1.6226		748
Synonymous	-6.24	170	93.3	1.82	0.00000660	813
Loss of Function	-0.311	22	20.5	1.07	0.00000105	229

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000397	0.000396
Ashkenazi Jewish	0.00	0.00
East Asian	0.000278	0.000278
Finnish	0.00	0.00
European (Non-Finnish)	0.000212	0.000212
Middle Eastern	0.000278	0.000278
South Asian	0.000425	0.000425
Other	0.000165	0.000165

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Putative oxidoreductase. Acts as a tumor suppressor and plays a role in apoptosis. Required for normal bone development (By similarity). May function synergistically with p53/TP53 to control genotoxic stress-induced cell death. Plays a role in TGFB1 signaling and TGFB1-mediated cell death. May also play a role in tumor necrosis factor (TNF)-mediated cell death. Inhibits Wnt signaling, probably by sequestering DVL2 in the cytoplasm. {ECO:0000250, ECO:0000269|PubMed:11719429, ECO:0000269|PubMed:15070730, ECO:0000269|PubMed:15548692, ECO:0000269|PubMed:16061658, ECO:0000269|PubMed:16219768, ECO:0000269|PubMed:19366691, ECO:0000269|PubMed:19465938}.
• Disease: DISEASE: Note=Defects in WWOX may be involved in several cancer types. The gene spans the second most common chromosomal fragile site (FRA16D) which is frequently altered in cancers (PubMed:10861292). Alteration of the expression and expression of some isoforms is associated with cancers. However, it is still unclear if alteration of WWOX is directly implicated in cancerogenesis or if it corresponds to a secondary effect (PubMed:10861292, PubMed:11572989, PubMed:15266310, PubMed:15073125, PubMed:15131042). {ECO:0000269|PubMed:10861292, ECO:0000269|PubMed:11572989, ECO:0000269|PubMed:15073125, ECO:0000269|PubMed:15131042, ECO:0000269|PubMed:15266310}.; DISEASE: Esophageal cancer (ESCR) [MIM:133239]: A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage. {ECO:0000269|PubMed:11956080}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia, autosomal recessive, 12 (SCAR12) [MIM:614322]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR12 is additionally characterized by onset of generalized seizures in infancy, and delayed psychomotor development with mental retardation. Some patients may also show spasticity. {ECO:0000269|PubMed:24369382, ECO:0000269|PubMed:24456803}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 28 (EIEE28) [MIM:616211]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:25411445}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;p73 transcription factor network;ErbB4 signaling events;Activation of the TFAP2 (AP-2) family of transcription factors;Negative regulation of activity of TFAP2 (AP-2) family transcription factors;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Nuclear signaling by ERBB4;Signaling by ERBB4;Signaling by Receptor Tyrosine Kinases (Consensus)

Recessive Scores

• pRec: 0.982

Intolerance Scores

• loftool: 0.304
• rvis_EVS: 1.1
• rvis_percentile_EVS: 91.92

Haploinsufficiency Scores

• pHI: 0.489
• hipred: Y
• hipred_score: 0.564
• ghis: 0.566

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.445

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	Medium
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Wwox
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); immune system phenotype; skeleton phenotype; liver/biliary system phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; growth/size/body region phenotype; neoplasm; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: wwox
• Affected structure: whole organism
• Phenotype tag: abnormal
• Phenotype quality: decreased length

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;osteoblast differentiation;steroid metabolic process;Wnt signaling pathway;negative regulation of Wnt signaling pathway;positive regulation of transcription by RNA polymerase II;skeletal system morphogenesis;oxidation-reduction process;cellular response to transforming growth factor beta stimulus;intrinsic apoptotic signaling pathway by p53 class mediator;extrinsic apoptotic signaling pathway;positive regulation of extrinsic apoptotic signaling pathway;positive regulation of extrinsic apoptotic signaling pathway in absence of ligand
• Cellular component: nucleus;cytoplasm;mitochondrion;Golgi apparatus;cytosol;plasma membrane;microvillus;RNA polymerase II transcription factor complex
• Molecular function: transcription coactivator activity;protein binding;oxidoreductase activity;enzyme binding;protein dimerization activity;cofactor binding;coenzyme binding