FBXO38
protein-codingF-box protein 38, the group of F-boxes other
Gene summary
This gene encodes a large protein that contains an F-box domain and may participate in protein ubiquitination. The encoded protein is a transcriptional co-activator of Krueppel-like factor 7 (Klf7). A heterozygous mutation in this gene was found in individuals with autosomal dominant distal hereditary motor neuronopathy type IID. There is a pseudogene for this gene on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~58.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014259
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0018894
Submitter: ClinGen
FBXO38 was first reported in relation to autosomal dominant distal hereditary motor neuropathy (dHMN) in 2013 (Sumner et al., PMID: 24207122). dHMN, with variable age of onset and severity, presents with primary features of calf weakness and slowly progressive weakness of both distal and proximal leg and arm muscles. FBXO38, F-Box only protein 38, is expressed in the human brain, spinal cord, and skeletal muscle. The function is hypothesized to include 1) ubiquitination, through acting as a subunit of the SCF (Skp1-cullin-Fbox) E3 ubiquitin ligase complex and 2) as a transcription factor by acting as a coactivator of Kruppel-like factor 7 (KLF7), a member of the KLF family of zinc finger transcription factors, that plays critical roles in axonal outgrowth and regeneration. The mechanism of pathogenicity is not yet established but at least one report suggested loss of function. Two variants, reported in 3 probands in 2 publications (PMIDs: 24207122, 34103343), are included in this curation. The first variant was identified in a large family with 4+ generations of affected individuals. Extensive segregation data was collected, which was consistent with gene-disease association (15 affected individuals tested positive, 24 unaffected individuals tested negative, no conflicting evidence). This variant was then found in an additional unrelated proband and their similarly affected parent. A second variant was identified in an individual with juvenile-onset upper limb distal weakness. Both variants are located in a highly conserved nuclear export signal region. Of note, a homozygous variant was reported in a consanguineous individual with early onset slowly progressive distal motor neuronopathy accompanied by hearing loss and multiple organ anomalies; heterozygous parents and a maternal aunt were asymptomatic (PMID: 31420593). This publication was not included in this curation due to lack of functional evidence. The disease-gene association appears to be moderate with the combined genetic and experimental evidence indicating a score of 9.5 for FBXO38 and autosomal dominant distal hereditary motor neuropathy. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.
Inheritance Pattern: AD
Disease ID:MONDO:0015352
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014259
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014259
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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 FBXO38 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_205836.3. 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 | 165 | 5 | 177 | ||
| missense | 2 | 402 | 45 | 3 | 452 | |
| nonsense | 9 | 9 | ||||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 7 | 7 | ||||
| Total | 2 | 0 | 431 | 210 | 8 | 651 |
Highest pathogenic variant AF is 0.000020445363
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_995308.1 | 21 | MANE Select | |
| Ensembl | ENSP00000342023.6 | 21 | MANE Select | |
| RefSeq | NP_001258652.1 | 20 | Standard | |
| RefSeq | NP_110420.3 | 21 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- positive regulation of neuron projection development
Cellular Component
- nucleus
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394370
- Coding exons
- 21
- Length
- 58902
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 15
- Defined
- 125748
- p
- 0.0000596
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.81 | 425 | 622 | 0.683 | 0.0000338 | 7364 |
| Missense (PolyPhen) | 260 | 419.68 | 0.61952 | 5006 | ||
| Synonymous | 0.563 | 204 | 214 | 0.951 | 0.0000114 | 2073 |
| Loss of Function | 6.05 | 9 | 59.2 | 0.152 | 0.00000354 | 672 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000072 | 0.000070 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation. May coactivate KLF7, but does not seem to promote KLF7 ubiquitination (By similarity). {ECO:0000250}.;
- Disease
- DISEASE: Neuronopathy, distal hereditary motor, 2D (HMN2D) [MIM:615575]: A disorder characterized by onset of slowly progressive distal lower limb weakness and atrophy between the second and fourth decades of life. Weakness usually begins in the calf muscles and later involves more proximal muscles. The severity is variable, and some patients have difficulty walking or running. Most also have upper limb involvement, particularly of the triceps and intrinsic hand muscles. Some patients may lose independent ambulation later in the disease course. Sensory impairment is typically not present, and cognition and bulbar function are normal. {ECO:0000269|PubMed:24207122}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.108
Intolerance Scores
- LoFtool
- 0.508
- RVIS EVS
- -0.88
- RVIS percentile EVS
- 10.5
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.895
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |