C3
protein-codingcomplement C3, the group of Complement system activation components|Receptor ligands|C3 and PZP like, alpha-2-macroglobulin domain containing
Gene summary
Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients. [provided by RefSeq, Nov 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~52.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013417
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013043
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013892
Submitter: ClinGen
C3 was first reported in relation to autosomal dominant C3 Glomerulopathy (C3G) in 2010 (Martínez-Barricarte et al., PMID: 20852386). 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:612925) and C3G. The split curation for autosomal dominant aHUS has been curated separately. Seventeen variants (missense) that have been reported in 17 probands in 7 publications (PMIDs: 20852386, 21784901, 26283675, 26471127, 26895476, 29566171, 37615951) are included in this curation. The mechanism of pathogenicity is known to be gain of function (GOF), causing the score of variants’ functional evidence to be upgraded when in support of this mechanism. This gene-disease association is also supported by protein interaction with CFH, functional alteration demonstrated on alternative pathway (AP) hemolysis assay, and biochemical function involving C3 nephritic factor (C3NeF) (PMIDs: 379217, 9291131, 21784901). 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 January 17, 2024 (SOP Version 10.1).
Inheritance Pattern: AD
Disease ID:MONDO:0013043
Submitter: ClinGen
C3 was first reported in relation to autosomal dominant atypical hemolytic uremic syndrome (aHUS) in 2008 (Frémeaux-Bacchi et al., PMID: 18796626). 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: 612925) and C3 glomerulopathy (C3G) (OMIM: 613779). The split curation for semidominant C3G will be conducted separately. Thirteen variants (missense) that have been reported in thirteen probands in three publications (PMIDs: 18796626, 25608561, 26826462) 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 reported to be gain of function. This gene-disease relationship is also supported by biochemical function in the complement mediated immune response, protein interaction with CFH and CFI, and a mouse model phenocopying disease in humans (PMIDs: 9291131, 21285368, 30714990). In summary, there is definitive evidence supporting the relationship between C3 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 August 3, 2023 (SOP Version 9).
Inheritance Pattern: AR
Disease ID:MONDO:0013417
Submitter: Laboratory for Molecular Medicine
This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.
Inheritance Pattern: AR
Disease ID:MONDO:0013417
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Dermatologic; Hematologic; Ophthalmologic;Renal
Intervention: Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic; Renal
Rationale: In Complement component 3 deficiency, individuals may manifest with frequent infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Individuals may develop renal disease, and awareness may allow early management of renal sequelaentiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; 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)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to C3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000064.4. 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 | 29 | 354 | 5 | 388 | ||
| missense | 18 | 839 | 23 | 2 | 882 | |
| nonsense | 13 | 11 | 7 | 31 | ||
| start loss | 0 | |||||
| frameshift | 14 | 10 | 3 | 27 | ||
| splice donor/acceptor (+/-2bp) | 5 | 18 | 19 | 42 | ||
| Total | 32 | 57 | 897 | 377 | 7 | 1370 |
Highest pathogenic variant AF is 0.00014684851
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000055.2 | 41 | MANE Select | |
| Ensembl | ENSP00000245907.4 | 41 | MANE Select | |
| Ensembl | ENSP00000512087.1 | 3 | Standard | |
| Ensembl | ENSP00000469744.1 | 7 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| c3a.1 | Danio rerio | Structure: whole organism Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
- Pertussis - Homo sapiens (human)
- Legionellosis - Homo sapiens (human)
- Systemic lupus erythematosus - Homo sapiens (human)
Biological Process
- positive regulation of type IIa hypersensitivity
- positive regulation of protein phosphorylation
- positive regulation of activation of membrane attack complex
- proteolysis
- fatty acid metabolic process
Molecular Function
- serine-type endopeptidase activity
- endopeptidase inhibitor activity
- signaling receptor binding
- protein binding
- C5L2 anaphylatoxin chemotactic receptor binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
- plasma membrane
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000245907
- Coding exons
- 41
- Length
- 52859
- Individuals with no LoFs
- 125706
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125748
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.75 | 720 | 960 | 0.750 | 0.0000648 | 10871 |
| Missense (PolyPhen) | 160 | 271.92 | 0.5884 | 3068 | ||
| Synonymous | -1.59 | 442 | 401 | 1.10 | 0.0000297 | 3245 |
| Loss of Function | 7.01 | 19 | 91.3 | 0.208 | 0.00000513 | 1036 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00025 | 0.00025 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00024 | 0.00024 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.; FUNCTION: C3-beta-c: Acts as a chemoattractant for neutrophils in chronic inflammation. {ECO:0000250}.;
- Disease
- DISEASE: Complement component 3 deficiency (C3D) [MIM:613779]: A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis. {ECO:0000269|PubMed:7961791}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Macular degeneration, age-related, 9 (ARMD9) [MIM:611378]: 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:17634448, ECO:0000269|PubMed:24036952}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Hemolytic uremic syndrome atypical 5 (AHUS5) [MIM:612925]: 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:18796626, ECO:0000269|PubMed:20513133}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype.; DISEASE: Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.;
Intolerance Scores
- LoFtool
- 0.335
- RVIS EVS
- -1.69
- RVIS percentile EVS
- 2.62
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.961
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |