WAC
protein-codingWW domain containing adaptor with coiled-coil
Gene summary
The protein encoded by this gene contains a WW domain, which is a protein module found in a wide range of signaling proteins. This domain mediates protein-protein interactions and binds proteins containing short linear peptide motifs that are proline-rich or contain at least one proline. This gene product shares 94% sequence identity with the WAC protein in mouse, however, its exact function is not known. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~90.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014741
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014741
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018760
Submitter: ClinGen
The *WAC* gene encodes a multi-functional protein that plays a role in coupling H2B monoubiquitination with transcription elongation, starvation-induced autophagy, golgi biogenesis, functional augmin complex, and regulation of energy-mediated mTORC1 activity. Additionally, it is highly expressed in the postnatal brain. *WAC* was first reported in relation to autosomal dominant Desanto-Shinawi syndrome in 2015 (DeSanto et al., PMID:26264232). This disorder is characterized by a spectrum of neurodevelopmental phenotypes including speech and language difficulties, motor delays, intellectual disability, behavioral issues and seizures, as well as extra-neurological features including growth delay, heart defects, hearing loss, and kidney abnormalities. Additionally, this disorder is associated with distinctive facial features including prominent forehead, deep-set eyes, depressed nasal bridge, bulbous nasal dip, and bushy eyebrows. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Desanto-Shinawi syndrome (MONDO:0018760): WAC-related facial dysmorphism-developmental delay-behavioral abnormalities syndrome and facial dysmorphism-developmental delay-behavioral abnormalities syndrome due to *WAC* point mutation. Six variants (including frameshift and nonsense) that have been reported in six probands in three publications (PMIDs: 25356899, 26264232, 26757981) are included in this curation. More evidence is available in the literature (PMIDs: 23033978, 29663678, 29928181, 32214004, 33123400, 33387902, 34997803, 34797027, 35636632, 35018708), but the maximum score for genetic evidence (12 pts.) has been reached. The vast majority of reported variants are *de novo*, with five variants reported to be due to confirmed or suspected parental germline mosaicisim. There are several recurrent variants that have been reported in more than one unrelated patient including: c.374C>A, p.(Ser125*); c.381+4_381+7delAGTA, p.(Gly92Alafs*2); c.1648C>T, p.(Arg550*); c.1661_1664del, p.(Ser554*). The mechanism of pathogenicity is known to be heterozygous loss-of-function (LOF). This gene-disease relationship is also supported by drosophila model studies (PMID: 26757981) which demonstrated that RNAi induced knockdown of WAC expression caused an altered behavioral phenotype in a drosophila light-off jump reflex habituation test. Additionally, there is a preprint manuscript available at bioRxiv (https://doi.org/10.1101/2022.01.24.477600) in which a constitutive mouse *Wac* model has been generated and capitulates many of the phenotypes observed in humans. In summary, there is definitive evidence to support the relationship between *WAC* and autosomal dominant Desanto-Shinawi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability/Autism expert panel on 11/10/2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0014741
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014741
Submitter: Illumina
WAC was first reported in relation to autosomal dominant Desanto-Shinawi syndrome in 2014 (25356899: Hamdan et al. 2014). At least six de novo, loss of function unique variants have been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least six probands from three publications (25356899; 26264232; 26757981). Germline mosaicism has been reported. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency. Expression data and an animal model are available, however, there is insufficient information to score either piece of experimental evidence (26757981). In summary, there is strong genetic evidence to support the relationship between WAC and Desanto-Shinawi syndrome, autosomal dominant. Additional functional evidence is needed to reach a definitive classification.
Inheritance Pattern: AD
Disease ID:MONDO:0014741
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Gastrointestinal; Neurologic; Ophthalmologic
Intervention: General
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to WAC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016628.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 5 | 17 | 3 | 25 | ||
| missense | 1 | 1 | 151 | 33 | 5 | 191 |
| nonsense | 27 | 11 | 3 | 41 | ||
| start loss | 0 | |||||
| frameshift | 56 | 14 | 3 | 73 | ||
| splice donor/acceptor (+/-2bp) | 9 | 8 | 9 | 26 | ||
| Total | 93 | 34 | 171 | 50 | 8 | 356 |
Highest pathogenic variant AF is 0.0000013803118
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057712.2 | 14 | MANE Select | |
| Ensembl | ENSP00000346986.4 | 14 | MANE Select | |
| RefSeq | NP_567822.1 | 12 | Standard | |
| RefSeq | NP_567823.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Post-translational protein modification
- Metabolism of proteins
- Protein ubiquitination
- E3 ubiquitin ligases ubiquitinate target proteins
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
Molecular Function
- RNA polymerase II complex binding
- chromatin binding
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- spliceosomal complex
- nuclear speck
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000354911
- Coding exons
- 14
- Length
- 90620
- Individuals with no LoFs
- 124747
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 124751
- p
- 0.0000160
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.51 | 262 | 341 | 0.769 | 0.0000171 | 4199 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000018 | 0.000018 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- 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}.;
Recessive Scores
- pRec
- 0.125
Intolerance Scores
- LoFtool
- 0.325
- RVIS EVS
- -0.87
- RVIS percentile EVS
- 10.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- N
- Indispensability score
- 0.466
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |