FBXW5
protein-codingF-box and WD repeat domain containing 5, the group of F-box and WD repeat domain containing|WD repeat domain containing
Gene summary
This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene contains WD-40 domains, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene, however, they were found to be nonsense-mediated mRNA decay (NMD) candidates, hence not represented. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~4.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FBXW5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018998.4. 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 | 1 | 3 | 5 | ||
| missense | 165 | 4 | 169 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 0 | 0 | 168 | 5 | 3 | 176 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_061871.1 | 8 | MANE Select | |
| Ensembl | ENSP00000313034.3 | 8 | MANE Select | |
| Ensembl | ENSP00000404829.1 | 4 | Standard | |
| Ensembl | ENSP00000394011.1 | 3 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of toll-like receptor signaling pathway
- Post-translational protein modification
- Metabolism of proteins
- Chaperonin-mediated protein folding
- Immune System
Biological Process
- protein polyubiquitination
- regulation of mitotic nuclear division
- regulation of centrosome duplication
- protein ubiquitination
- SCF-dependent proteasomal ubiquitin-dependent protein catabolic process
Molecular Function
- ubiquitin-protein transferase activity
- protein binding
- protein kinase binding
Cellular Component
- cytoplasm
- cytosol
- SCF ubiquitin ligase complex
- Cul4-RING E3 ubiquitin ligase complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000325285
- Coding exons
- 8
- Length
- 4262
- Individuals with no LoFs
- 125499
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 81
- Defined
- 125580
- p
- 0.000323
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.90 | 506 | 399 | 1.27 | 0.0000295 | 3627 |
| Missense (PolyPhen) | 200 | 167.53 | 1.1938 | 1609 | ||
| Synonymous | -4.72 | 267 | 185 | 1.44 | 0.0000151 | 1156 |
| Loss of Function | -0.346 | 23 | 21.3 | 1.08 | 9.17e-7 | 225 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.00029 | 0.00029 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00040 | 0.00038 | rare |
| Finnish | 0.000047 | 0.000046 | rare |
| European (Non-Finnish) | 0.00041 | 0.00040 | rare |
| South Asian | 0.00050 | 0.00049 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Substrate recognition component of both SCF (SKP1-CUL1- F-box protein) and DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes. Substrate recognition component of the SCF(FBXW5) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of SASS6 during S phase, leading to prevent centriole reduplication. The SCF(FBXW5) complex also mediates ubiquitination and degradation of actin-regulator EPS8 during G2 phase, leading to the transient degradation of EPS8 and subsequent cell shape changes required to allow mitotic progression. Substrate-specific adapter of the DCX(FBXW5) E3 ubiquitin-protein ligase complex which mediates the polyubiquitination and subsequent degradation of TSC2. May also act as a negative regulator of MAP3K7/TAK1 signaling in the interleukin-1B (IL1B) signaling pathway. {ECO:0000269|PubMed:18381890, ECO:0000269|PubMed:19232515, ECO:0000269|PubMed:21725316}.;
Recessive Scores
- pRec
- 0.120
Intolerance Scores
- LoFtool
- 0.759
- RVIS EVS
- -1.28
- RVIS percentile EVS
- 5.19
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.980
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |