FBXO22

Chr 15AR

F-box protein 22

Also known as: FBX22, FISTC1, TYMAS

NCBI Gene: 26263 ENSG00000167196 UniProt: Q8NEZ5 OMIM: 609096

The protein functions as a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes, promoting proteasomal degradation of key sarcomeric proteins including alpha-actinin and filamin-C, and regulating histone methylation through control of histone demethylase levels. Mutations cause Tayoun-Maawali syndrome with autosomal recessive inheritance. The gene is highly constrained against loss-of-function variation (pLI 0.98, LOEUF 0.30), indicating that biallelic variants are likely to have significant clinical impact.

OMIM ResearchSummary from RefSeq, OMIM, 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 and, as a transcriptional target of the tumor protein p53, is thought to be involved in degradation of specific proteins in response to p53 induction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2010]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Tayoun-Maawali syndromeMIM #621184

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Tayoun-Maawali 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.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.30

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.30LOEUF

pLI 0.977

Z-score 3.48

OE 0.06 (0.02–0.30)

Highly constrained

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

Missense Constraint?

0.84Z-score

OE missense 0.84 (0.75–0.95)

188 obs / 223.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.06 (0.02–0.30)

0≤0.351.4

Missense OE?0.84 (0.75–0.95)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 1 / 16.0Missense obs/exp: 188 / 223.2Syn Z: -0.60

Background carrier burden — how many people carry a rare variant somewhere in FBXO22?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

484 rare PASS variants

Rare truncating (LoF)

1 in 2,300

55 rare PASS variants

Rare synonymous (reference)

1 in 180

209 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FBXO22. 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 240	1 in 2,700
South Asian	~43k	1 in 140	1 in 2,900
Remaining (unassigned)	~30k	1 in 130	1 in 2,000
European (Finnish)	~27k	1 in 400	1 in 4,400
Admixed American	~22k	1 in 130	1 in 1,000
African / African American	~21k	1 in 150	≈ 1 in 17,000
East Asian	~20k	1 in 100	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,600	1 in 740
Middle Eastern	~2,884	1 in 120	1 in 570

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): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓