FBXW4

protein-coding

F-box and WD repeat domain containing 4, the group of F-box and WD repeat domain containing|WD repeat domain containing

Gene summary

This gene is a member of the F-box/WD-40 gene family, which recruit specific target proteins through their WD-40 protein-protein binding domains for ubiquitin mediated degradation. In mouse, a highly similar protein is thought to be responsible for maintaining the apical ectodermal ridge of developing limb buds; disruption of the mouse gene results in the absence of central digits, underdeveloped or absent metacarpal/metatarsal bones and syndactyly. This phenotype is remarkably similar to split hand-split foot malformation in humans, a clinically heterogeneous condition with a variety of modes of transmission. An autosomal recessive form has been mapped to the chromosomal region where this gene is located, and complex rearrangements involving duplications of this gene and others have been associated with the condition. A pseudogene of this locus has been mapped to one of the introns of the BCR gene on chromosome 22. [provided by RefSeq, Jul 2008]

Previous symbols:

SHFM3

MANE transcript

NM_022039.4

Inheritance

ClinVar variants

U:103B:21

Top phenotype

Split hand-foot malformation 3

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr10:101,610,664-101,695,295

External References & Databases

Ensembl (ENSG00000107829)

Transcript & Mutation Effects

hg38 • Region Span ~84.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

split hand-foot malformation 3LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0009525

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBXW4 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 63

not providedTotal: 60

Split hand-foot malformation 3Total: 30

FBXW4-related disorderTotal: 7

See casesTotal: 2

human split-hand/foot malformation type 3Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022039.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	11 clinvar	3 clinvar	18
missense			89 clinvar	4 clinvar	2 clinvar	95
nonsense			2 clinvar	1 clinvar		3
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	103	16	5	124

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022039.4	RefSeq	NP_071322.2	9	MANE Select
ENST00000331272.9	Ensembl	ENSP00000359149.3	9	MANE Select
NM_001323541.2	RefSeq	NP_001310470.1	8	Standard
ENST00000664783.1	Ensembl	ENSP00000499522.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fbxw4	Danio rerio	Structure: pigment cell Quality: irregular spatial pattern abnormal

Gene / Model

Organism

Observed Phenotype

fbxw4

Danio rerio

Structure: pigment cell

Quality: irregular spatial pattern

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Chaperonin-mediated protein folding
Immune System
Association of TriC/CCT with target proteins during biosynthesis

Biological Process

protein polyubiquitination
positive regulation of mesenchymal cell proliferation
ubiquitin-dependent protein catabolic process
Wnt signaling pathway
embryonic limb morphogenesis

Molecular Function

molecular_function
ubiquitin-protein transferase activity
protein binding

Cellular Component

ubiquitin ligase complex
cytosol
SCF ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331272
Coding exons: 9
Length: 84630
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.43	167	228	0.734	0.0000130	2622
Missense (PolyPhen)		42	56.464	0.74384		596
Synonymous	0.814	83	93.0	0.893	0.00000520	848
Loss of Function	2.53	9	21.7	0.414	0.00000130	217

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably recognizes and binds to some phosphorylated proteins and promotes their ubiquitination and degradation. Likely to be involved in key signaling pathways crucial for normal limb development. May participate in Wnt signaling.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.459
RVIS EVS: -0.63
RVIS percentile EVS: 17.03

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.645

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium