WDR36
protein-codingWD repeat domain 36, the group of UTPb subcomplex|WD repeat domain containing
Gene summary
This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Mutations in this gene have been associated with adult-onset primary open-angle glaucoma (POAG). [provided by RefSeq, Jul 2008]
- GLC1G
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~38.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012357
Submitter: PanelApp Australia
Inheritance Pattern: Unknown
Disease ID:MONDO:0012357
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012357
Submitter: ClinGen
WDR36 was first reported in relation to autosomal dominant primary open angle glaucoma G in 2005 (Monemi et al., 2005, PMID: 15677485). The study reported linkage to WDR36 in 7 families with primary open angle glaucoma and identifed four variants that were predicted to be disease causing. However, the variants are not supported by functional evidence -- they are found at relatively high population frequencies in gnomAD. This gene-disease association has been studied in several case-control studies (PMID: 28658128, 29104481, 22025897, 18172102, 16723468, 19347049, 29540704, 17353431, 28282485, 19875670, 16876519); however, statistical significance was not reached in most. A meta-analysis (Liu et al, 2017; PMID: 28658128) including 5 individual studies reported no statistically significant association of WDR36 variants with primary open angle glaucoma. WDR36 is expressed ubiquitously, including th eye (PMID: 15677485). The function of WDR36 is not clearly understood, but animal studies suggest a role in eye development. Zebrafish and mouse models show head and eye phenotypes (PMID: 20631153, 18469340); however, they are non-specific and do not support the role of WDR36 variation in glaucoma. With an unclear role for this gene in glaucoma, it is thought to have a modifier effect in disease (PMID: 29104481). In summary, the evidence supporting the relationship between WDR36 and autosomal dominant primary open angle glaucoma has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role WDR36 plays in glaucoma, but based on the evidence avaialble at this time, the gene is disputed as a monogenic cause of glaucoma.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to WDR36 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_139281.3. 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 | 1 | 13 | 7 | 21 | ||
| missense | 1 | 178 | 10 | 3 | 192 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 1 | 183 | 23 | 10 | 217 |
Highest pathogenic variant AF is 0.0005131476
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_644810.2 | 23 | MANE Select | |
| Ensembl | ENSP00000424628.3 | 23 | MANE Select | |
| Ensembl | ENSP00000526341.1 | 23 | Standard | |
| Ensembl | ENSP00000526341.1 | 23 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| wdr36 | Danio rerio | Structure: retinal ganglion cell Quality: increased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ribosome biogenesis in eukaryotes - Homo sapiens (human)
- rRNA processing
- Metabolism of RNA
- rRNA modification in the nucleus and cytosol
- rRNA processing in the nucleus and cytosol
Biological Process
- retina homeostasis
- rRNA processing
- visual perception
- biological_process
- regulation of axon extension
Molecular Function
- RNA binding
Cellular Component
- cellular_component
- nucleoplasm
- nucleolus
- small-subunit processome
- Pwp2p-containing subcomplex of 90S preribosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000506538
- Coding exons
- 23
- Length
- 38787
- Individuals with no LoFs
- 125719
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 29
- Defined
- 125748
- p
- 0.000115
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.80 | 616 | 503 | 1.23 | 0.0000245 | 6212 |
| Missense (PolyPhen) | 156 | 158.27 | 0.98564 | 1997 | ||
| Synonymous | -2.69 | 223 | 177 | 1.26 | 0.00000864 | 1844 |
| Loss of Function | 4.64 | 16 | 52.1 | 0.307 | 0.00000256 | 635 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in the nucleolar processing of SSU 18S rRNA. Involved in T-cell activation and highly coregulated with IL2. {ECO:0000269|PubMed:21051332}.;
- Disease
- DISEASE: Glaucoma 1, open angle, G (GLC1G) [MIM:609887]: A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. {ECO:0000269|PubMed:15677485, ECO:0000269|PubMed:18172102}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.143
Intolerance Scores
- LoFtool
- 0.439
- RVIS EVS
- 0.03
- RVIS percentile EVS
- 55.86
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.893
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |