FBXO45

Chr 3

F-box protein 45

Also known as: Fbx45

NCBI Gene: 200933 ENSG00000174013 UniProt: P0C2W1 OMIM: 609112

FBXO45 encodes a component of E3 ubiquitin ligase complexes that targets specific proteins for degradation and is required for normal neuromuscular synaptogenesis, axon pathfinding, and neuronal migration during brain development. Mutations cause autosomal recessive developmental and epileptic encephalopathy with severe intellectual disability and early-onset seizures. This neurodevelopmental disorder primarily affects the central nervous system with onset in infancy or early childhood.

OMIM ResearchSummary from RefSeq, UniProt

Members of the F-box protein family, such as FBXO45, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (summary by Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Jan 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.27

Clinical Summary— FBXO45

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

17 VUS of 21 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.971

Z-score 3.06

OE 0.00 (0.00–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.34Z-score

OE missense 0.44 (0.36–0.55)

62 obs / 139.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.27)

0≤0.351.4

Missense OE?0.44 (0.36–0.55)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 0 / 10.9Missense obs/exp: 62 / 139.9Syn Z: 0.68

This gene — mechanism propensity

0.18100th %ile

GOF

0.3788th %ile

LOF

0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.27

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

21 submitted variants in ClinVar

ClinVar

Classification Summary

VUS17

Benign3

VUS

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	17	0	17
Likely Benign	0	0	0
Benign	0	3	3
Total	17	3	20

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

88 pathogenic / likely-pathogenic (of 106) ClinVar copy-number / structural variants overlap FBXO45 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →