FBXW8

protein-coding

F-box and WD repeat domain containing 8, the group of F-box and WD repeat domain containing|WD repeat domain containing

Gene summary

This gene encodes a member of the F-box protein family, members of which are 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 three 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 contains a WD-40 domain, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

FBXO29

MANE transcript

NM_153348.3

Inheritance

—

ClinVar variants

U:97B:12

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr12:116,910,950-117,032,498

External References & Databases

Ensembl (ENSG00000174989)

Transcript & Mutation Effects

hg38 • Region Span ~121.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBXW8 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 98

not providedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153348.3. 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				1 clinvar	2 clinvar	3
missense			94 clinvar	6 clinvar	3 clinvar	103
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	97	7	5	109

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153348.3	RefSeq	NP_699179.2	11	MANE Select
ENST00000652555.1	Ensembl	ENSP00000498999.1	11	MANE Select
NM_012174.2	RefSeq	NP_036306.1	11	Standard
ENST00000309909.10	Ensembl	ENSP00000310686.6	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Post-translational protein modification
Metabolism of proteins
Immune System
Adaptive Immune System

Biological Process

protein polyubiquitination
Golgi organization
cell population proliferation
protein ubiquitination
post-translational protein modification

Molecular Function

ubiquitin-protein transferase activity
protein binding

Cellular Component

Golgi apparatus
cytosol
SCF ubiquitin ligase complex
Cul7-RING ubiquitin ligase complex
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000309909
Coding exons: 11
Length: 120193
Individuals with no LoFs: 124889
Homozygous LoFs: 3
Heterozygous LoFs: 856
Defined: 125748
p: 0.00342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.119	322	328	0.982	0.0000201	3881
Missense (PolyPhen)		78	79.708	0.97857		909
Synonymous	0.204	133	136	0.978	0.00000996	1187
Loss of Function	0.446	25	27.5	0.908	0.00000136	309

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0020	0.0020	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0.0012	0.0012	notable
East Asian	0.0012	0.0011	notable
Finnish	0.0053	0.0053	notable
European (Non-Finnish)	0.0054	0.0054	notable
South Asian	0.00039	0.00039	rare
Other	0.0024	0.0024	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Substrate-recognition component of a Cul7-RING ubiquitin-protein ligase complex, which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The Cul7-RING(FBXW8) complex mediates ubiquitination and consequent degradation of GORASP1, acting as a component of the ubiquitin ligase pathway that regulates Golgi morphogenesis and dendrite patterning in brain (PubMed:21572988). Mediates ubiquitination and degradation of IRS1 in a mTOR-dependent manner: the Cul7-RING(FBXW8) complex recognizes and binds IRS1 previously phosphorylated by S6 kinase (RPS6KB1 or RPS6KB2) (PubMed:18498745). The Cul7-RING(FBXW8) complex also mediates ubiquitination of MAP4K1/HPK1: recognizes and binds autophosphorylated MAP4K1/HPK1, leading to its degradation, thereby affecting cell proliferation and differentiation (PubMed:24362026). Associated component of the 3M complex, suggesting that it mediates some of 3M complex functions (PubMed:24793695). {ECO:0000269|PubMed:18498745, ECO:0000269|PubMed:21572988, ECO:0000269|PubMed:24362026, ECO:0000269|PubMed:24793695}.;

Recessive Scores

pRec: 0.274

Intolerance Scores

LoFtool: 0.995
RVIS EVS: -0.28
RVIS percentile EVS: 33.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.868

Gene Damage Prediction

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