CFB
protein-codingcomplement factor B, the group of Sushi domain containing|Complement system activation components
Gene summary
This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is cleaved by complement factor D yielding the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease which associates with C3b to form the alternative pathway C3 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their proliferation. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. This cluster includes several genes involved in regulation of the immune reaction. Polymorphisms in this gene are associated with a reduced risk of age-related macular degeneration. The polyadenylation site of this gene is 421 bp from the 5' end of the gene for complement component 2. [provided by RefSeq, Jul 2008]
- BFD
- BF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013892
Submitter: ClinGen
The relationship between CFB and C3 glomerulopathy was evaluated on 7 March 2024 using the ClinGen Clinical Validity Framework. CFB codes for a single chain glycoprotein that is a component of the alternative complement pathway, is cleaved by Factor D, and where the C3bBb molecule represents the alternate pathway convertase. CFB was first reported associated with C3 glomerulopathy by Imamura et al (PMID: 25758434). Only three pathogenic variants associated with C3 glomerulonephritis have been reported, two of which have been described previously in atypical Haemolytic uremic syndrome. These variants are missense changes with functional data supporting pathogenicity and have been reported in different publications over time. The mechanism of pathogenicity is Gain of Function. This gene-disease association for CFB is also supported by biochemical function, protein interactions, altered biochemical function in affected individuals, and by functional alteration in a cell culture model. In summary, CFB has a limited association with C3 glomerulopathy. The association has been demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The Expert panel expect that the association will be confirmed more robustly with the demonstration of more CFB variants in patients with C3 glomerulopathy.
Inheritance Pattern: AD
Disease ID:MONDO:0013042
Submitter: ClinGen
CFB was first reported in relation to autosomal dominant atypical haemolytic uraemic syndrome (aHUS) in 2007 (Goicoechea de Jorge et al, PMID: 17182750). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability associated with CFB. The diseases were split into separate entities: aHUS (with autosomal dominant inheritance due to a Gain of Function variant, OMIM612924) and CFB deficiency (due to autosomal recessive disease and two loss of function variants, OMIM 615561). CFB deficiency will be curated by the Immunodeficiency GCEP. The relationship between CFB and aHUS was evaluated using the ClinGen Clinical Validity Framework. The CFB gene encodes a single chain glycoprotein that is a component of the alternative complement pathway. It is cleaved by Factor D into fragments Ba and Bb, and the C terminal half of Bb has serine protease activity that cleaves C3 into C3a and C3b. CFB is a circulating molecule, and is expressed mainly in the liver. The clinical presentation of aHUS is with microangiopathic haemolytic anaemia, thrombocytopenia, and renal failure, without a gastrointestinal infection, and often progressing to kidney failure. Eight variants, all missense, have been reported in four publications and are included in this curation (PMIDs: 17182750; 24652797; 32540405; 32540405). Only pathogenic variants due to missense changes in CFB with functional data supporting a gain of function effect are scored here. The same variants reported in multiple possibly-unrelated individuals are not scored separately. However segregation data are available from three families with aHUS and different heterozygous pathogenic variants in CFB for which there is supporting functional data (PMIDs: 32540405; 24906628; 17182750). The gene-disease association is further supported by experimental data from the interaction of CFB with C3 (which is also associated with aHUS), CFB function that is likely to explain the clinical phenotype, as well as in vitro studies demonstrating that the pathogenic CFB variants affect CFB function. In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Complement Mediated Kidney Diseases GCEP on the meeting date May 17, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0014255
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013042
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: Unknown
Disease ID:MONDO:0013042
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013042
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Renal
Intervention: Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic; Renal
Rationale: In hemolytic-uremic syndrome, the choice of specific treatment modalities (eg, danazol, plasma exchange, plasma therapy), as well as decision to perform renal transplant, may be dictated by genetic diagnosis, and certain agents/precipitating factors should be avoided (eg, certain medications); In Complement factor B deficiency, individuals may manifest with severe and recurrent infections due to encapsulated bacteria, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CFB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001710.6. 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 | 11 | 121 | 1 | 133 | ||
| missense | 6 | 5 | 294 | 17 | 322 | |
| nonsense | 12 | 1 | 13 | |||
| start loss | 0 | |||||
| frameshift | 1 | 13 | 14 | |||
| splice donor/acceptor (+/-2bp) | 1 | 8 | 9 | |||
| Total | 6 | 7 | 338 | 139 | 1 | 491 |
Highest pathogenic variant AF is 0.000007524516
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001701.2 | 18 | MANE Select | |
| Ensembl | ENSP00000416561.2 | 18 | MANE Select | |
| Ensembl | ENSP00000417793.1 | 3 | Standard | |
| Ensembl | ENSP00000419887.2 | 16 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Staphylococcus aureus infection - Homo sapiens (human)
- Human Complement System
- Dengue-2 Interactions with Complement and Coagulation Cascades
- Complement Activation
Biological Process
- proteolysis
- complement activation
- complement activation, alternative pathway
- regulation of complement activation
Molecular Function
- complement binding
- serine-type endopeptidase activity
- protein binding
Cellular Component
- extracellular region
- extracellular space
- plasma membrane
- extracellular exosome
- blood microparticle
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000425368
- Coding exons
- 18
- Length
- 24387
- Individuals with no LoFs
- 125722
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 26
- Defined
- 125748
- p
- 0.000103
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.48 | 326 | 410 | 0.794 | 0.0000253 | 5006 |
| Missense (PolyPhen) | 92 | 143.83 | 0.63966 | 1707 | ||
| Synonymous | 0.734 | 145 | 157 | 0.925 | 0.00000982 | 1447 |
| Loss of Function | 3.99 | 14 | 41.9 | 0.334 | 0.00000231 | 501 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000066 | 0.000062 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00016 | rare |
| Finnish | 0.000092 | 0.000092 | rare |
| European (Non-Finnish) | 0.00012 | 0.00011 | rare |
| South Asian | 0.000099 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B- lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B-lymphocytes.;
- Disease
- DISEASE: Hemolytic uremic syndrome atypical 4 (AHUS4) [MIM:612924]: An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. {ECO:0000269|PubMed:17182750, ECO:0000269|PubMed:20513133}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.; DISEASE: Complement factor B deficiency (CFBD) [MIM:615561]: An immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. {ECO:0000269|PubMed:24152280}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.370
- RVIS EVS
- 1.64
- RVIS percentile EVS
- 96.15
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.928
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |