FBXW11

Chr 5AD

F-box and WD repeat domain containing 11

Also known as: BTRC2, BTRCP2, FBW1B, FBXW1B, Fbw11, Hos, NEDJED

NCBI Gene: 23291 ENSG00000072803 UniProt: Q9UKB1 OMIM: 605651

This gene encodes a substrate recognition component of the SCF ubiquitin ligase complex that targets phosphorylated proteins for degradation, regulating critical pathways including Wnt signaling, NF-kappa-B activation, circadian rhythms, and mTORC1 signaling. Mutations cause a neurodevelopmental disorder with intellectual disability, developmental delay, seizures, and behavioral abnormalities, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.98, LOEUF 0.31), indicating that haploinsufficiency is likely not tolerated in the general population.

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 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 Fbws class and, in addition to an F-box, contains multiple WD40 repeats. This gene contains at least 14 exons, and its alternative splicing generates 3 transcript variants diverging at the presence/absence of two alternate exons. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental, jaw, eye, and digital syndromeMIM #618914

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neurodevelopmental, jaw, eye, and digital syndrome; no ClinGen or GenCC tier

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.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.31

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.31LOEUF

pLI 0.976

Z-score 4.56

OE 0.15 (0.08–0.31)

Highly constrained

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

Missense Constraint?

3.96Z-score

OE missense 0.37 (0.32–0.43)

115 obs / 311.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.31)

0≤0.351.4

Missense OE?0.37 (0.32–0.43)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 33.5Missense obs/exp: 115 / 311.5Syn Z: 0.39

Background carrier burden — how many people carry a rare variant somewhere in FBXW11?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 340

371 rare PASS variants

Rare truncating (LoF)

1 in 14,000

29 rare PASS variants

Rare synonymous (reference)

1 in 220

256 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FBXW11. 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 330	1 in 22,000
South Asian	~43k	1 in 380	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 280	none seen
European (Finnish)	~27k	1 in 860	≈ 1 in 13,000
Admixed American	~22k	1 in 460	1 in 4,400
African / African American	~21k	1 in 290	≈ 1 in 21,000
East Asian	~20k	1 in 230	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,600	none seen
Middle Eastern	~2,884	≈ 1 in 720	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): 12 of 13 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 12 of 13 (exon 7 below).? see exons ↓