GeneBe

FBXW7

protein-coding

F-box and WD repeat domain containing 7, the group of MicroRNA protein coding host genes|F-box and WD repeat domain containing|WD repeat domain containing

Gene summary

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 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 was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations in this gene are detected in ovarian and breast cancer cell lines, implicating the gene's potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

MANE transcript

NM_001349798.2

Inheritance

AD

ClinVar variants

P:33U:163B:45

Top phenotype

developmental delay, hypotonia, and impaired language

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr4:152,320,544-152,536,092

External References & Databases

Ensembl (ENSG00000109670)NCBI Gene (55294)OMIM (606278)HGNC:16712GenCCUniProt (Q969H0)AlphaFoldClinVar (FBXW7)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~215.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, hypotonia, and impaired languageSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859280

Submitter: Labcorp Genetics (formerly Invitae)

developmental delay, hypotonia, and impaired languageSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859280

Submitter: PanelApp Australia

developmental delay, hypotonia, and impaired languageMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859280

Submitter: G2P

developmental delay, hypotonia, and impaired languageSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859280

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBXW7 variants in ClinVar

12 Conditions Cataloged
not providedTotal: 171
Inborn genetic diseasesTotal: 47
Developmental delay, hypotonia, and impaired languageTotal: 33
FBXW7-related disorderTotal: 31
not specifiedTotal: 20
Neurodevelopmental disorderTotal: 3
EBV-positive nodal T- and NK-cell lymphomaTotal: 1
Pervasive developmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001349798.2. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
32
clinvar
3
clinvar
 37
missense
5
clinvar
9
clinvar
151
clinvar
7
clinvar
3
clinvar
 175
nonsense
2
clinvar
4
clinvar
4
clinvar
 10
start loss
0
frameshift
5
clinvar
7
clinvar
1
clinvar
 13
splice donor/acceptor (+/-2bp)
1
clinvar
5
clinvar
 6
Total1320163396241

Highest pathogenic variant AF is 0.0000013882795

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001349798.2RefSeqNP_001336727.111MANE Select
ENST00000281708.10EnsemblENSP00000281708.311MANE Select
NM_001013415.2RefSeqNP_001013433.111Standard
NM_001257069.1RefSeqNP_001243998.11Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fbxw7Danio rerio

Structure: glioblast (sensu Vertebrata)

Quality: increased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ubiquitin mediated proteolysis - Homo sapiens (human)
  • NOTCH-Ncore
  • Parkin-Ubiquitin Proteasomal System pathway
  • Pathways Affected in Adenoid Cystic Carcinoma
  • Notch Signaling Pathway

Biological Process

  • protein polyubiquitination
  • vasculogenesis
  • vasculature development
  • sister chromatid cohesion
  • Notch signaling pathway

Molecular Function

  • ubiquitin-protein transferase activity
  • protein binding
  • cyclin binding
  • protein binding, bridging
  • ubiquitin protein ligase binding

Cellular Component

  • nucleus
  • nucleoplasm
  • nucleolus
  • cytoplasm
  • mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000281708
Coding exons
11
Length
214844
Individuals with no LoFs
125603
Homozygous LoFs
0
Heterozygous LoFs
5
Defined
125608
p
0.0000199
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.711683680.4560.00001834646
Missense (PolyPhen)19137.510.138171663
Synonymous-0.03351341341.000.000006511339
Loss of Function5.23439.50.1010.00000237427

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000900.000087rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.00000940.0000088rare
South Asian00.0absent
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Substrate recognition component of a SCF (SKP1-CUL1-F- box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter bring them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:17434132, PubMed:26976582, PubMed:28727686). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NOTCH2, MCL1, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). SCF(FBXW7) complex mediates the ubiquitination and subsequent degradation of NFE2L1 (By similarity). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). {ECO:0000250|UniProtKB:Q8VBV4, ECO:0000269|PubMed:11565034, ECO:0000269|PubMed:11585921, ECO:0000269|PubMed:14739463, ECO:0000269|PubMed:15103331, ECO:0000269|PubMed:17434132, ECO:0000269|PubMed:17558397, ECO:0000269|PubMed:17873522, ECO:0000269|PubMed:22608923, ECO:0000269|PubMed:22748924, ECO:0000269|PubMed:25775507, ECO:0000269|PubMed:26976582, ECO:0000269|PubMed:28007894, ECO:0000269|PubMed:28727686, ECO:0000269|PubMed:29149593, ECO:0000305|PubMed:12354302}.;

Recessive Scores

pRec
0.622

Intolerance Scores

LoFtool
0.0563
RVIS EVS
-0.11
RVIS percentile EVS
45.36

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
S
Essential (gene trap)
K
Indispensability pred.
E
Indispensability score
0.973

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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