FBXW11

protein-coding

F-box and WD repeat domain containing 11, 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 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 belongs to the Fbws class and, in addition to an F-box, contains multiple WD40 repeats. This gene contains at least 14 exons, and its alternative splicing generates 3 transcript variants diverging at the presence/absence of two alternate exons. [provided by RefSeq, Jul 2008]

Previous symbols:

FBXW1B

MANE transcript

NM_001378974.1

Inheritance

ClinVar variants

P:11U:128B:9

Top phenotype

Neurodevelopmental, jaw, eye, and digital syndrome

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr5:171,861,549-172,006,873

External References & Databases

Ensembl (ENSG00000072803)

Transcript & Mutation Effects

hg38 • Region Span ~145.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental, jaw, eye, and digital syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030057

Submitter: Ambry Genetics

neurodevelopmental, jaw, eye, and digital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030057

Submitter: PanelApp Australia

neurodevelopmental, jaw, eye, and digital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030057

Submitter: G2P

syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: Orphanet

neurodevelopmental, jaw, eye, and digital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030057

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental, jaw, eye, and digital syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030057

Submitter: Illumina

The FBXW11 gene is located on chromosome 5 at 5q35.1 and encodes the F-box and WD repeat domain containing 11 protein. This F-box protein functions as part of a ubiquitin ligase complex and is involved in ubiquitin-mediated protein degradation. FBSW11 also participates in the Wnt/β-catenin and Hh signalling pathways, which play critical roles in early embryonic development and tissue patterning. FBXW11 was first reported in relation to autosomal dominant FBXW11-related neurodevelopmental, brain, jaw, eye and digital anomalies in 2019 (31402090: Holt et al. 2019). Evidence supporting this gene-disease relationship includes case-level data and expereimental data. Seven unique heterozygous missense variants in this gene have been reported in seven individuals in a single cross-institutional publication (31402090: Holt et al. 2019). All variants occurred de novo. The maximum score for genetic evidence (12 pts) has been reached. Structural analyses indicated the variants clustered at the surface of the substrate-binding domain of FBXW11 and were predicted to destabilize the protein and/or its interactions, but the mechansim of disease has not yet been definitively determined. This gene-disease relationship is also supported by the gene's role in the Hh and Wnt/β-catenin signalling pathways, in which multiple genes have been linked to similar clinical phenotypes, tissue expression in the clinically affected systems in both humans and zebrafish, and a zebrafish knockdown model that shows eye, jaw, and pectoral fin anomalies that correlate with the phenotypes observed in humans (31402090: Holt et al. 2019). In summary, there is strong evidence to support the relationship between FBXW11 and autosomal dominant neurodevelopmental, brain, eye, and digit anomalies. Additional reports in humans published three years from the first proposal of the association are needed to reach a definitive classification.

Clinical Genomic Database (CGD)

Neurodevelopmental, jaw, eye, and digital syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31402090

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBXW11 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 90

not specifiedTotal: 36

Neurodevelopmental, jaw, eye, and digital syndromeTotal: 28

FBXW11-related disorderTotal: 8

FBXW11-related neurodevelopmental, brain, eye, and digit anomaliesTotal: 1

FBXW11-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378974.1. 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	8 clinvar		9
missense	1 clinvar	10 clinvar	99 clinvar	1 clinvar		111
nonsense			10 clinvar			10
start loss						0
frameshift			11 clinvar			11
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	1	10	128	9	0	148

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378974.1	RefSeq	NP_001365903.1	13	MANE Select
ENST00000517395.6	Ensembl	ENSP00000428753.2	13	MANE Select
NM_001378975.1	RefSeq	NP_001365904.1	12	Standard
NM_001378976.1	RefSeq	NP_001365905.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Circadian rhythm - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Ubiquitin mediated proteolysis - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Shigellosis - Homo sapiens (human)

Biological Process

G2/M transition of mitotic cell cycle
protein polyubiquitination
protein dephosphorylation
Wnt signaling pathway
protein ubiquitination

Molecular Function

ubiquitin-protein transferase activity
protein binding
protein dimerization activity
ubiquitin protein ligase activity

Cellular Component

ubiquitin ligase complex
nucleus
centrosome
cytosol
SCF ubiquitin ligase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265094
Coding exons: 12
Length: 145325
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125735
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.96	115	312	0.369	0.0000179	3539
Missense (PolyPhen)		21	121.22	0.17324		1380
Synonymous	0.392	107	112	0.953	0.00000595	1024
Loss of Function	4.56	5	33.5	0.149	0.00000195	369

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

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. Probably recognizes and binds to phosphorylated target proteins. SCF(FBXW11) mediates the ubiquitination of phosphorylated CTNNB1 and participates in Wnt signaling. SCF(FBXW11) mediates the ubiquitination of phosphorylated NFKBIA, which degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription. SCF(FBXW11) mediates the ubiquitination of IFNAR1. SCF(FBXW11) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (PubMed:25503564). Involved in the oxidative stress-induced a ubiquitin-mediated decrease in RCAN1. Mediates the degradation of CDC25A induced by ionizing radiation in cells progressing through S phase and thus may function in the intra-S- phase checkpoint. Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and phosphorylated PER2. SCF(FBXW11) mediates the ubiquitination of CYTH1, and probably CYTH2 (PubMed:29420262). {ECO:0000269|PubMed:10321728, ECO:0000269|PubMed:10437795, ECO:0000269|PubMed:10644755, ECO:0000269|PubMed:10648623, ECO:0000269|PubMed:14532120, ECO:0000269|PubMed:14603323, ECO:0000269|PubMed:15917222, ECO:0000269|PubMed:18575781, ECO:0000269|PubMed:19966869, ECO:0000269|PubMed:20347421, ECO:0000269|PubMed:25503564, ECO:0000269|PubMed:29420262}.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.354
RVIS EVS: -0.47
RVIS percentile EVS: 23.04

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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