FOXD3
protein-codingforkhead box D3, the group of Forkhead boxes
Gene summary
This gene belongs to the forkhead family of transcription factors which is characterized by a distinct forkhead domain. Mutations in this gene cause autoimmune susceptibility 1. [provided by RefSeq, Nov 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~2.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019503
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019172
Submitter: ClinGen
*FOXD3* was first reported in relation to autosomal dominant aniridia in 2012 (Kloss et al, 2012; PMID: 22815627). The study reported 4 families with anterior segment dysgenesis/Peters anomaly/aniridia and identifed four variants that were predicted to be disease causing. However, the variants are not supported by functional evidence, and they are found at relatively high population frequencies in gnomAD. There are no additional case reports; however, several studies refer to *FOXD3* in relation to aniridia based on the first report by Kloss et al (PMID: 22815627). *FOXD3* is shown to be expressed in the periocular mesenchyme (PMID: 32528955). The function of **FOXD3** is not clearly understood, but animal studies suggest a role in neural crest specification, migration and survival (PMID: 16499899). Zebrafish studies show that **foxd3**-positive cell population that migrates into the anterior segment in the late embryonic and early larval stages (PMID: 33182738). *Foxd3* knock out in mice result in embryonic lethality (PMID: 12381664). In summary, the evidence supporting the relationship between **FOXD3** and autosomal dominant aniridia has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role **FOXD3** plays in aniridia.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FOXD3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_012183.3. 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 | 7 | 7 | ||||
| missense | 89 | 1 | 90 | |||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 89 | 7 | 1 | 97 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_036315.1 | 1 | MANE Select | |
| Ensembl | ENSP00000360157.2 | 1 | MANE Select |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| foxd3 | Danio rerio | Structure: iridophore Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neural Crest Differentiation
- POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
- Wnt Signaling Pathway and Pluripotency
- Developmental Biology
- POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation
Biological Process
- negative regulation of transcription by RNA polymerase II
- in utero embryonic development
- regulation of transcription by RNA polymerase II
- anatomical structure morphogenesis
- cell differentiation
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- protein binding
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000371116
- Coding exons
- 1
- Length
- 2068
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.951 | 158 | 195 | 0.809 | 0.00000916 | 2953 |
| Missense (PolyPhen) | 24 | 53.281 | 0.45045 | 628 | ||
| Synonymous | -0.758 | 99 | 89.9 | 1.10 | 0.00000465 | 1076 |
| Loss of Function | 2.08 | 1 | 6.91 | 0.145 | 2.98e-7 | 103 |
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 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Binds to the consensus sequence 5'-A[AT]T[AG]TTTGTTT-3' and acts as a transcriptional repressor. Also acts as a transcriptional activator. Promotes development of neural crest cells from neural tube progenitors. Restricts neural progenitor cells to the neural crest lineage while suppressing interneuron differentiation. Required for maintenance of pluripotent cells in the pre-implantation and peri-implantation stages of embryogenesis. {ECO:0000269|PubMed:11891324}.;
Recessive Scores
- pRec
- 0.224
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 |