CFI
protein-codingcomplement factor I, the group of Complement system regulators and receptors|Scavenger receptor cysteine rich domain containing
Gene summary
This gene encodes a serine proteinase that is essential for regulating the complement cascade. The encoded preproprotein is cleaved to produce both heavy and light chains, which are linked by disulfide bonds to form a heterodimeric glycoprotein. This heterodimer can cleave and inactivate the complement components C4b and C3b, and it prevents the assembly of the C3 and C5 convertase enzymes. Defects in this gene cause complement factor I deficiency, an autosomal recessive disease associated with a susceptibility to pyogenic infections. Mutations in this gene have been associated with a predisposition to atypical hemolytic uremic syndrome, a disease characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Primary glomerulonephritis with immune deposits and age-related macular degeneration are other conditions associated with mutations of this gene. [provided by RefSeq, Dec 2015]
- IF
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~71.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0012594
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014189
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0013041
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0016244
Submitter: ClinGen
CFI was first reported in relation to autosomal dominant atypical hemolytic uremic syndrome (aHUS) in 2004 (Fremeaux-Bacchi et al., PMID: 15173250). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following diseases have been split into separate entities, aHUS (OMIM: 612923) and C3 glomerulopathy (C3G) (OMIM: 610984). The split curation for autosomal dominant C3G will be conducted separately. Thirteen variants (missense, nonsense, and frameshift) that have been reported in thirteen probands in four publications (PMIDs: 15173250, 15917334, 17597211, 20016463) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function, causing dysregulation of the complement mediated immune pathway. This gene-disease relationship is also supported by biochemical functions indicating the role of CFI in the complement pathway and protein interaction with CFH (PMID: 28671664). Of note, enrichment of CFI rare genetic variants has been demonstrated in aHUS in two studies using burden type testing (PMIDs: 29500241, 30377230). It should also be noted that a recent analysis of the genotyping data from UK biobank aimed to identify CFI variants that are known to result in low levels of factor I and identified no cases of aHUS with any of the 1,671 type 1 variants, demonstrating very low penetrance for CFI. In summary, there is definitive evidence supporting the relationship between CFI and autosomal dominant aHUS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Complement Mediated Kidney Diseases GCEP on the meeting date June 1, 2023 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0013041
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0007471
Submitter: Orphanet
Inheritance Pattern: Unknown
Disease ID:MONDO:0014189
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013892
Submitter: ClinGen
CFI was first reported in relation to autosomal dominant C3 glomerulopathy (C3G) in 2012 (Servais et al., PMID: 22456601). C3G is characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment (Smith et al., 2019, PMID: 30692664). The term C3G is inclusive of dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, the following disease entities have been split into multiple disease entities, atypical hemolytic uremic syndrome (aHUS) (OMIM:612923) and C3G. The split curation for autosomal dominant aHUS has been curated separately. Seven variants (missense, nonsense, and frameshift) that have been reported in 7 probands in 3 publications (PMIDs: 22456601, 35619721, 37615951) are included in this curation. The mechanism of pathogenicity is known to be loss of function, causing dysregulation of the complement-mediated immune pathway. This gene-disease relationship is also supported by biochemical function in the complement-mediated immune pathway, protein interaction with factor H, functional alteration demonstrated by reduced *in vitro* expression in HEK293T cells and low FI plasma levels caused by variants observed in patients, and a mouse model recapitulating C3G as seen in human patients (PMIDs: 28671664, 32510551, 34149444). 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 April 17, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0012594
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic; Renal
Intervention: Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic; Renal
Rationale: In Hemolytic-uremic syndrome, atypical, the choice of specific treatment modalities (eg, danazol, plasma exchange, plasma therapy, eculizumab), as well as decision to perform renal transplant, may be dictated by genetic diagnosis (though renal transplant has been described as not uniformly successful), and certain agents/precipitating factors should be avoided (eg, certain medications); In Complement factor I deficiency, antiinfectious prophylaxis and early and aggressive treatment of infections can be beneficial; Medical considerations relevant for Hemolytic uremic syndrome (caused by variants in the same gene) may also be important for individuals diagnosed with Complement factor I deficiency
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CFI variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000204.5. 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 | 1 | 9 | 106 | 2 | 119 |
| missense | 7 | 76 | 352 | 25 | 3 | 463 |
| nonsense | 13 | 13 | 3 | 29 | ||
| start loss | 1 | 1 | ||||
| frameshift | 22 | 14 | 2 | 38 | ||
| splice donor/acceptor (+/-2bp) | 3 | 15 | 4 | 22 | ||
| Total | 46 | 120 | 370 | 131 | 5 | 672 |
Highest pathogenic variant AF is 0.0001135627
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000195.3 | 13 | MANE Select | |
| Ensembl | ENSP00000378130.2 | 13 | MANE Select | |
| RefSeq | NP_001304986.2 | 14 | Standard | |
| RefSeq | NP_001317964.1 | 12 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cfi | Danio rerio | Structure: hyaloid vessel Quality: decreased diameter abnormal |
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 and Coagulation Cascades
Biological Process
- proteolysis
- receptor-mediated endocytosis
- complement activation, classical pathway
- regulation of complement activation
- innate immune response
Molecular Function
- serine-type endopeptidase activity
- scavenger receptor activity
- protein binding
- metal ion binding
Cellular Component
- extracellular region
- extracellular space
- membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394634
- Coding exons
- 13
- Length
- 61484
- Individuals with no LoFs
- 125667
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 81
- Defined
- 125748
- p
- 0.000322
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.201 | 298 | 308 | 0.968 | 0.0000158 | 3865 |
| Missense (PolyPhen) | 96 | 103.62 | 0.92647 | 1219 | ||
| Synonymous | -1.55 | 127 | 107 | 1.19 | 0.00000586 | 1027 |
| Loss of Function | 2.67 | 18 | 35.1 | 0.513 | 0.00000194 | 403 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00064 | 0.00064 | rare |
| Ashkenazi Jewish | 0.00040 | 0.00040 | rare |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00032 | 0.00032 | rare |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.00098 | 0.00098 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Responsible for cleaving the alpha-chains of C4b and C3b in the presence of the cofactors C4-binding protein and factor H respectively.;
- Disease
- DISEASE: Complement factor I deficiency (CFI deficiency) [MIM:610984]: Autosomal recessive condition associated with a propensity to pyogenic infections. {ECO:0000269|PubMed:12562389, ECO:0000269|PubMed:17018561, ECO:0000269|PubMed:8613545}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 13 (ARMD13) [MIM:615439]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:23685748}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.157
- RVIS EVS
- 0.82
- RVIS percentile EVS
- 88.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.502
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |