ODAD3
protein-codingouter dynein arm docking complex subunit 3, the group of Outer dynein arm docking complex subunits
Gene summary
This gene encodes a protein containing coiled-coil domains. The encoded protein functions in outer dynein arm assembly and is required for motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]
- CCDC151
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~15.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014465
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014465
Submitter: ClinGen
*ODAD3* (*CCDC151*) was first reported in relation to autosomal recessive primary ciliary dyskinesia 30 (PCD30) in (Hjeij et al., PMID: 25192045). PCD30 is one of nearly 50 primary ciliary dyskinesias that have been observed to be inherited in a monogenic fashion. Most PCD patients present with a chronic productive cough, recurrent respiratory infection, and chronic rhinosinusitis. Some patients also demonstrate situs inversus and neonatal respiratory distress (PMID:33242470). 7 variants (3 nonsense, 1 deletion, 2 out-of-frame duplications, and 1 out-of-frame indel) that have been reported in 7 probands in 7 publications (PMIDs: 25192045, 31469207, 32490514, 31213628, 25224326, 33719352, 30504913) are included in this curation. One variant (NM_145045.5:c.925G>T [p.E309*]) is suspected to be a founder variant with origin in the Middle East/Northern Africa (PMID:31469207) despite its absence from gnomAD (v.2.1.1). To date, the p.E309* variant has been observed in 6 patients with PCD30 from 3 families. Of thse 6 patients, 2 were from Egypt, 2 were from Israel, and 2 were reportedly of Arabic/Bedouin ancestry. Only 1 proband with this variant was scored as a part of this curation due to the assertion that p.E309* is a founder variant. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be LOF. This gene-disease relationship is also supported by expression studies, biochemical evidence, protein interactions, animal models, and a rescue experiment (PMIDs: 23715323, 25192045, 24067530). First, GTEx data showed high levels of expression of *ODAD3* in human tissues associated with PCD (lungs, testis, fallopian tubes) (PMID: 23715323). Next, Jerber et al. demonstrated that *Ccdc151* expression was shown to be strongly induced in mouse ependymal cells in vitro during the ciliary differentiation process. The level of expression of *Ccdc151* reached almost 7x higher than the comparison protein (Tpb) in ciliogenesis, which strongly suggests that *CCDC151* is important for the structure and function of cilia (PMID: 24067530). Hjeij et al. performed a co-immunoprecipitation which showed that *ODAD3* interacts physically with *ODAD1* in vitro (2019). Furthermore, they showed that the localization of *ODAD1* to the ciliary axonnome is dependent on the presence of *ODAD3* (PMID:25192045). Since *ODAD1* was classified as definitively associated with PCD by the ClinGen Motile Ciliopathy GCEP, it is likely that LOF variants in *ODAD3* would result in PCD as well. Hjeij et al. also published a mouse model, zebrafish model, and zebrafish rescue experiment. Mice with the c.828+2T>C *Ccdc151* variant (identified within a mutagenesis screen) showed laterality defects as well as immotile cilia in the trachea and brain ventricles. TEM confirmed loss of the ODA in the tracheal cilia of the mice. The zebrafish models contained a c.631T>A (p.Lys211*) variant in *ccdc151* which was also discovered as part of a mutagenesis screen. These zebrafish demonstrated laterality defects and kidney cysts. High speed video microscopy revealed ciliary immotility in the developing kidney of the zebrafish. The laterality defects were partially rescued by inserting a wild-type copy of *ccdc151* into zebrafish embryos (PMID:25192045). In summary, *ODAD3* is definitively associated with autosomal recessive primary ciliary dyskinesia 30. 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 Motile Ciliopathy GCEP on 2/28/2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014465
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016575
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Musculoskeletal; Pulmonary
Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Cardiovascular; Pulmonary
Rationale: Pulmonary and audiologic surveillance may be beneficial to assess respiratory and hearing function and institute early management measures; In order to facilitate mucus clearance, aggressive interventions (eg, chest percussion and oscillatory vest), as well as vaccinations and early and aggressive treatment of respiratory infections may be beneficial, though measures including lobectomy or lung transplantation may be necessary; Individuals may require surgery or other interventions related to congenital cardiac malformations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ODAD3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_145045.5. 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 | 91 | 1 | 92 | |||
| missense | 165 | 9 | 4 | 178 | ||
| nonsense | 8 | 7 | 1 | 16 | ||
| start loss | 0 | |||||
| frameshift | 10 | 4 | 14 | |||
| splice donor/acceptor (+/-2bp) | 8 | 2 | 10 | |||
| Total | 18 | 19 | 168 | 100 | 5 | 310 |
Highest pathogenic variant AF is 0.000076302065
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_659482.3 | 13 | MANE Select | |
| Ensembl | ENSP00000348757.3 | 13 | MANE Select | |
| RefSeq | NP_001289382.1 | 13 | Standard | |
| RefSeq | NP_001289383.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ccdc151 | Danio rerio | Structure: post-vent region Quality: curved ventral abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- cilium movement
- determination of left/right symmetry
- outer dynein arm assembly
- regulation of cilium assembly
Molecular Function
- protein binding
Cellular Component
- centriole
- cilium
- axoneme
- ciliary basal body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000356392
- Coding exons
- 13
- Length
- 15332
- Individuals with no LoFs
- 124752
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 55
- Defined
- 124807
- p
- 0.000220
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.644 | 328 | 362 | 0.905 | 0.0000206 | 3863 |
| Missense (PolyPhen) | 83 | 101.56 | 0.81725 | 1126 | ||
| Synonymous | 0.714 | 139 | 150 | 0.926 | 0.00000807 | 1152 |
| Loss of Function | 1.04 | 26 | 32.4 | 0.803 | 0.00000157 | 359 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.000093 | 0.000093 | rare |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Ciliary protein involved in outer dynein arm assembly and required for motile cilia function. {ECO:0000250|UniProtKB:Q8BSN3}.;
- Disease
- DISEASE: Ciliary dyskinesia, primary, 30 (CILD30) [MIM:616037]: A disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia. Patients may exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. {ECO:0000269|PubMed:25192045, ECO:0000269|PubMed:25224326}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.412
- RVIS EVS
- 0.82
- RVIS percentile EVS
- 88.02
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.455
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |