FBXW10

Chr 17

F-box and WD repeat domain containing 10

Also known as: Fbw10, HREP, SM25H2, SM2SH2

NCBI Gene: 10517 ENSG00000171931 UniProt: Q5XX13 OMIM: 611679

FBXW10 encodes a substrate-recognition component of SCF E3 ubiquitin ligase complexes that target specific proteins for degradation through ubiquitination. Mutations cause autosomal recessive intellectual disability with microcephaly, short stature, and facial dysmorphism. The gene shows minimal constraint against loss-of-function variants (pLI near 0), consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Members of the F-box protein family, such as FBXW10, 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 (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.12

Clinical Summary— FBXW10

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 VUS of 10 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.12LOEUF

pLI 0.000

Z-score 0.86

OE 0.87 (0.69–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.00Z-score

OE missense 0.88 (0.82–0.95)

498 obs / 565.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.87 (0.69–1.12)

0≤0.351.4

Missense OE?0.88 (0.82–0.95)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 45 / 51.6Missense obs/exp: 498 / 565.2Syn Z: 0.03

This gene — mechanism propensity

0.5869th %ile

GOF

0.6832th %ile

LOF

0.4332th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

10 submitted variants in ClinVar

ClinVar

Classification Summary

VUS1

Likely Benign2

Benign1

VUS

Likely Benign

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	1	0	1
Likely Benign	0	2	2
Benign	1	0	1
Total	2	2	4

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

View in ClinVar →

102 pathogenic / likely-pathogenic (of 116) ClinVar copy-number / structural variants overlap FBXW10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →