FBXO6

Chr 1

F-box protein 6

Also known as: FBG2, FBS2, FBX6, Fbx6b

NCBI Gene: 26270 ENSG00000116663 UniProt: Q9NRD1 OMIM: 605647

This gene encodes an F-box protein that serves as a substrate-recognition component of SCF-type E3 ubiquitin ligase complexes, targeting misfolded glycoproteins in the endoplasmic reticulum for degradation and regulating DNA damage response by promoting degradation of activated CHEK1. Biallelic mutations cause autosomal recessive developmental delay with seizures and microcephaly. The gene shows tolerance to loss-of-function variants (pLI 0.015), suggesting recessive inheritance requires complete loss of function from both alleles.

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, and its C-terminal region is highly similar to that of rat NFB42 (neural F Box 42 kDa) which may be involved in the control of the cell cycle. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.84

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.84LOEUF

pLI 0.015

Z-score 1.97

OE 0.40 (0.21–0.84)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.25Z-score

OE missense 1.05 (0.93–1.19)

190 obs / 180.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.40 (0.21–0.84)

0≤0.351.4

Missense OE?1.05 (0.93–1.19)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 5 / 12.5Missense obs/exp: 190 / 180.5Syn Z: -0.18

Background carrier burden — how many people carry a rare variant somewhere in FBXO6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

393 rare PASS variants

Rare truncating (LoF)

1 in 2,700

55 rare PASS variants

Rare synonymous (reference)

1 in 190

140 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FBXO6. 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 180	1 in 3,400
South Asian	~43k	1 in 120	1 in 3,900
Remaining (unassigned)	~30k	1 in 56	1 in 2,500
European (Finnish)	~27k	1 in 340	≈ 1 in 13,000
Admixed American	~22k	1 in 110	1 in 1,200
African / African American	~21k	1 in 94	1 in 2,300
East Asian	~20k	1 in 160	1 in 800
Ashkenazi Jewish	~13k	1 in 540	none seen
Middle Eastern	~2,884	1 in 160	≈ 1 in 2,900

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 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓