IFT122
protein-codingintraflagellar transport 122, the group of IFT-A complex|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. This cytoplasmic protein contains seven WD repeats and an AF-2 domain which function by recruiting coregulatory molecules and in transcriptional activation. Mutations in this gene cause cranioectodermal dysplasia-1. A related pseudogene is located on chromosome 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]
- WDR10
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~90.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0021093
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0021093
Submitter: ClinGen
IFT122 was first reported in relation to autosomal recessive Cranioectodermal dysplasia 1 (OMIM:218330) in 2010 (Walczak-Sztulpa et al., PMID: 20493458). This is a multisystem ciliopathy, with skeletal and ectodermal involvement. Seventeen variants (10 missense, 4 frameshift, 1 deletion, 2 intronic) have been reported in 10 probands in 6 publications (PMIDs: 20493458, 24689072, 26792575, 29037998, 23826986, 33717254). These variants support autosomal recessive inheritance and have been included in this curation. There is insufficient data available to score segregation in this curation. The mechanism of pathogenicity is reported to be LOF. This gene-disease association is also supported by mouse and zebra fish animal models (PMIDs: 19000668, 20493458). In vitro functional assays in patient and non-patients cells were supportive for the role of IFT122 gene in the number and length of cilia (PMID: 20493458, 24689072) and reduced interaction with IFT-A subunits in cells with CED1 missense variants (PMID: 29220510). In summary, IFT122 is definitively associated with autosomal recessive Cranioectodermal dysplasia 1 (OMIM:218330). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time (2010 to 2021).
Inheritance Pattern: AR
Disease ID:MONDO:0021093
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009032
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0021093
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dental; Dermatologic; Musculoskeletal
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 IFT122 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_052989.3. 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 | 23 | 191 | 3 | 217 | ||
| missense | 2 | 13 | 434 | 32 | 481 | |
| nonsense | 13 | 15 | 1 | 29 | ||
| start loss | 0 | |||||
| frameshift | 20 | 19 | 3 | 42 | ||
| splice donor/acceptor (+/-2bp) | 1 | 18 | 5 | 24 | ||
| Total | 36 | 65 | 466 | 223 | 3 | 793 |
Highest pathogenic variant AF is 0.00012482097
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_443715.1 | 30 | MANE Select | |
| Ensembl | ENSP00000324005.4 | 30 | MANE Select | |
| RefSeq | NP_001267470.1 | 30 | Standard | |
| RefSeq | NP_001267474.1 | 24 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ift122 | Danio rerio | Structure: hair cell Quality: disorganized abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Signal Transduction
- Hedgehog ,off, state
- Signaling by Hedgehog
- Intraflagellar transport
- Cilium Assembly
Biological Process
- neural tube closure
- signal transduction downstream of smoothened
- embryonic body morphogenesis
- negative regulation of smoothened signaling pathway involved in ventral spinal cord patterning
- embryonic heart tube development
Molecular Function
- protein binding
Cellular Component
- nucleoplasm
- cytosol
- cilium
- membrane
- intraciliary transport particle A
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000296266
- Coding exons
- 31
- Length
- 80231
- Individuals with no LoFs
- 125598
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 149
- Defined
- 125748
- p
- 0.000597
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.346 | 689 | 715 | 0.964 | 0.0000455 | 8514 |
| Missense (PolyPhen) | 215 | 227.67 | 0.94435 | 2656 | ||
| Synonymous | 0.364 | 275 | 283 | 0.972 | 0.0000180 | 2433 |
| Loss of Function | 2.56 | 49 | 72.5 | 0.676 | 0.00000375 | 871 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00098 | 0.00098 | rare |
| Latino/Admixed American | 0.00093 | 0.00090 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00076 | 0.00076 | rare |
| Finnish | 0.00051 | 0.00051 | rare |
| European (Non-Finnish) | 0.00057 | 0.00056 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for cilia formation during neuronal patterning. Acts as a negative regulator of Shh signaling. Required to recruit TULP3 to primary cilia (By similarity). {ECO:0000250}.;
Recessive Scores
- pRec
- 0.141
Intolerance Scores
- LoFtool
- 0.945
- RVIS EVS
- -1.27
- RVIS percentile EVS
- 5.21
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.500
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |