FBXO3

Chr 11

F-box protein 3

Also known as: FBA, FBX3

NCBI Gene: 26273 ENSG00000110429 UniProt: Q9UK99 OMIM: 609089

FBXO3 encodes a substrate recognition component of the SCF ubiquitin ligase complex that mediates targeted protein degradation, including regulation of p53 signaling and inflammatory responses. Mutations cause autosomal dominant developmental and epileptic encephalopathy with onset in infancy or early childhood. The gene is highly constrained against loss-of-function mutations (pLI 0.99, LOEUF 0.29), indicating that heterozygous variants can cause disease.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 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 belongs to the Fbxs class. Alternative splicing of this gene generates 2 transcript variants diverging at the 3' end. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.29

LOEUF· LoF intol.

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.29LOEUF

pLI 0.989

Z-score 4.52

OE 0.13 (0.06–0.29)

Highly constrained

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

Missense Constraint?

2.15Z-score

OE missense 0.63 (0.56–0.72)

168 obs / 266.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.13 (0.06–0.29)

0≤0.351.4

Missense OE?0.63 (0.56–0.72)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 4 / 31.3Missense obs/exp: 168 / 266.8Syn Z: 1.00

Background carrier burden — how many people carry a rare variant somewhere in FBXO3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

463 rare PASS variants

Rare truncating (LoF)

1 in 8,300

34 rare PASS variants

Rare synonymous (reference)

1 in 300

199 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FBXO3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 250	1 in 7,200
South Asian	~43k	1 in 150	1 in 7,000
Remaining (unassigned)	~30k	1 in 130	≈ 1 in 8,000
European (Finnish)	~27k	1 in 240	none seen
Admixed American	~22k	1 in 190	≈ 1 in 5,200
African / African American	~21k	1 in 210	≈ 1 in 5,900
East Asian	~20k	1 in 170	none seen
Ashkenazi Jewish	~13k	1 in 650	none seen
Middle Eastern	~2,884	1 in 410	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 9 of 11 coding exons well covered in gnomAD exomes; exons 6, 7 marginal. Genomes: all 11.? see exons ↓