FBXO11

protein-coding

F-box protein 11, the group of F-boxes other|Ubiquitin protein ligase E3 component n-recognins

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 Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

MANE transcript

NM_001190274.2

Inheritance

ClinVar variants

P:151U:361B:302

Top phenotype

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr2:47,789,316-47,906,498

External References & Databases

Ensembl (ENSG00000138081)

Transcript & Mutation Effects

hg38 • Region Span ~117.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060760

Submitter: G2P

intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060760

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060760

Submitter: PanelApp Australia

intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060760

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

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: 27620904; 29796876; 30057029

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBXO11 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 993

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalitiesTotal: 170

Inborn genetic diseasesTotal: 75

not specifiedTotal: 23

FBXO11-related disorderTotal: 23

Neurodevelopmental disorderTotal: 21

Intellectual disabilityTotal: 8

See casesTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001190274.2. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		1 clinvar	11 clinvar	204 clinvar	12 clinvar	228
missense	3 clinvar	68 clinvar	337 clinvar	74 clinvar	12 clinvar	494
nonsense	7 clinvar	8 clinvar	2 clinvar			17
start loss						0
frameshift	23 clinvar	15 clinvar	3 clinvar			41
splice donor/acceptor (+/-2bp)	11 clinvar	15 clinvar	8 clinvar			34
Total	44	107	361	278	24	814

Highest pathogenic variant AF is 0.000030796313

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001190274.2	RefSeq	NP_001177203.1	23	MANE Select
ENST00000403359.8	Ensembl	ENSP00000384823.4	23	MANE Select
NM_001374325.1	RefSeq	NP_001361254.1	22	Standard
NM_025133.4	RefSeq	NP_079409.3	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Post-translational protein modification
Metabolism of proteins
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation

Biological Process

protein polyubiquitination
cellular protein modification process
ubiquitin-dependent protein catabolic process
sensory perception of sound
protein ubiquitination

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding
protein-arginine N-methyltransferase activity

Cellular Component

ubiquitin ligase complex
nucleus
chromosome
nucleolus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000403359
Coding exons: 23
Length: 116478
Individuals with no LoFs: 125632
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125637
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.38	208	477	0.436	0.0000235	6136
Missense (PolyPhen)		33	191.33	0.17247		2342
Synonymous	-2.44	188	150	1.25	0.00000705	1682
Loss of Function	6.35	1	48.9	0.0205	0.00000255	622

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
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, such as DTL/CDT2, BCL6 and PRDM1/BLIMP1. The SCF(FBXO11) complex mediates ubiquitination and degradation of BCL6, thereby playing a role in the germinal center B-cells terminal differentiation toward memory B-cells and plasma cells. The SCF(FBXO11) complex also mediates ubiquitination and degradation of DTL, an important step for the regulation of TGF- beta signaling, cell migration and the timing of the cell-cycle progression and exit. Binds to and neddylates phosphorylated p53/TP53, inhibiting its transcriptional activity. SCF(FBXO11) does not seem to direct ubiquitination of p53/TP53. {ECO:0000269|PubMed:17098746, ECO:0000269|PubMed:22113614, ECO:0000269|PubMed:23478441, ECO:0000269|PubMed:23478445, ECO:0000269|PubMed:23892434, ECO:0000269|PubMed:24613396}.;
Disease: DISEASE: Note=Defects in FBXO11 may be a cause of diffuse large B- cell lymphoma by allowing the accumulation of BCL6, an oncoprotein that has a critical role in lymphomas. {ECO:0000269|PubMed:22113614}.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.112
RVIS EVS: -0.69
RVIS percentile EVS: 15.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

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