WAC

WW domain containing adaptor with coiled-coil

Basic information

Region (hg38): 10:28532493-28623112

Links

ENSG00000095787 ∙ NCBI:51322 ∙ OMIM:615049 ∙ HGNC:17327 ∙ Uniprot:Q9BTA9 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• DeSanto-Shinawi syndrome due to WAC point mutation (Strong), mode of inheritance: AD
• DeSanto-Shinawi syndrome due to WAC point mutation (Supportive), mode of inheritance: AD
• DeSanto-Shinawi syndrome due to WAC point mutation (Strong), mode of inheritance: AD
• DeSanto-Shinawi syndrome due to WAC point mutation (Definitive), mode of inheritance: AD
• DeSanto-Shinawi syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
DeSanto-Shinawi syndrome	AD	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	Craniofacial; Gastrointestinal; Neurologic; Ophthalmologic	25356899; 26264232

ClinVar

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

• not_provided (193 variants)
• DeSanto-Shinawi_syndrome_due_to_WAC_point_mutation (82 variants)
• Inborn_genetic_diseases (68 variants)
• not_specified (20 variants)
• WAC-related_disorder (19 variants)
• DeSanto-Shinawi_syndrome (6 variants)
• Intellectual_disability (5 variants)
• See_cases (4 variants)
• Neurodevelopmental_disorder (2 variants)
• WAC-related_neurodevelopmental_disorder (1 variants)
• Neurodevelopmental_delay (1 variants)
• Rare_genetic_intellectual_disability (1 variants)
• Neurodevelopmental_abnormality (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the WAC gene is commonly pathogenic or not. These statistics are base on transcript: NM_000016628.5. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	14	3	19
missense	1		118	27	6	152
nonsense	24	8	2			34
start loss						0
frameshift	49	10	2			61
splice donor/acceptor (+/-2bp)	9	8	3			20
Total	83	26	127	41	9

Highest pathogenic variant AF is 0.0000013803118

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
WAC	protein_coding	protein_coding	ENST00000354911	14	90620

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000294	124747	0	4	124751	0.0000160

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.51	262	341	0.769	0.0000171	4199
Missense in Polyphen		78	125.17	0.62317		1639
Synonymous	-0.416	133	127	1.05	0.00000714	1270
Loss of Function	5.53	0	35.6	0.00	0.00000196	405

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.000112	0.000110
Finnish	0.00	0.00
European (Non-Finnish)	0.0000183	0.0000177
Middle Eastern	0.000112	0.000110
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Acts as a linker between gene transcription and histone H2B monoubiquitination at 'Lys-120' (H2BK120ub1) (PubMed:21329877). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription (PubMed:21329877). Regulates the cell-cycle checkpoint activation in response to DNA damage (PubMed:21329877). Positive regulator of amino acid starvation- induced autophagy (PubMed:22354037). Also acts as a negative regulator of basal autophagy (PubMed:26812014). Positively regulates MTOR activity by promoting, in an energy-dependent manner, the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex. This leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). May negatively regulate the ubiquitin proteasome pathway (PubMed:21329877). {ECO:0000269|PubMed:21329877, ECO:0000269|PubMed:22354037, ECO:0000269|PubMed:26812014}.
• Disease: DISEASE: DeSanto-Shinawi syndrome (DESSH) [MIM:616708]: An autosomal dominant syndrome characterized by developmental delay, hypotonia, behavioral problems, eye abnormalities, constipation, feeding difficulties, seizures and sleep problems. Patients exhibit dysmorphic features, including broad/prominent forehead, synophrys and/or bushy eyebrows, depressed nasal bridge and bulbous nasal tip. Additional variable features are posteriorly rotated ears, hirsutism, deep-set eyes, thin upper lip, inverted nipples, hearing loss and branchial cleft anomalies. {ECO:0000269|PubMed:25356899, ECO:0000269|PubMed:26264232}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in WAC are the cause of a form of intellectual disability characterized by hypotonia, behavioral problems and distinctive facial dysmorphisms including a square- shaped face, deep set eyes, long palpebral fissures, and a broad mouth and chin. {ECO:0000269|PubMed:26757981}.
• Pathway: Post-translational protein modification;Metabolism of proteins;Protein ubiquitination;E3 ubiquitin ligases ubiquitinate target proteins (Consensus)

Recessive Scores

• pRec: 0.125

Intolerance Scores

• loftool: 0.325
• rvis_EVS: -0.87
• rvis_percentile_EVS: 10.73

Haploinsufficiency Scores

• pHI: 0.238
• hipred: Y
• hipred_score: 0.673
• ghis: 0.659

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: E
• gene_indispensability_pred: N
• gene_indispensability_score: 0.466

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Wac

Gene ontology

• Biological process: cellular response to DNA damage stimulus;histone monoubiquitination;positive regulation of macroautophagy;protein ubiquitination;negative regulation of proteasomal ubiquitin-dependent protein catabolic process;G1 DNA damage checkpoint;positive regulation of transcription, DNA-templated;histone H2B conserved C-terminal lysine ubiquitination
• Cellular component: nucleus;nucleoplasm;spliceosomal complex;nuclear speck
• Molecular function: RNA polymerase II complex binding;chromatin binding;protein binding