CFI

complement factor I, the group of Complement system regulators and receptors|Scavenger receptor cysteine rich domain containing

Basic information

Region (hg38): 4:109731008-109802150

Previous symbols: [ "IF" ]

Links

ENSG00000205403 ∙ NCBI:3426 ∙ OMIM:217030 ∙ HGNC:5394 ∙ Uniprot:P05156 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Doyne honeycomb retinal dystrophy (Supportive), mode of inheritance: AD
• complement factor I deficiency (Supportive), mode of inheritance: AR
• complement factor I deficiency (Strong), mode of inheritance: AR
• age related macular degeneration 13 (Limited), mode of inheritance: AD
• atypical hemolytic-uremic syndrome with I factor anomaly (Limited), mode of inheritance: AD
• atypical hemolytic-uremic syndrome with I factor anomaly (Strong), mode of inheritance: AD
• age related macular degeneration 13 (Limited), mode of inheritance: Unknown
• atypical hemolytic-uremic syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemolytic uremic syndrome, atypical; Complement factor I deficiency	AD/AR	Allergy/Immunology/Infectious; Hematologic; Pharmacogenomic; Renal	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	Allergy/Immunology/Infectious; Hematologic; Renal	4188976; 4097977; 4507613; 849647; 7922290; 8613545; 15173250; 16412054; 16175037; 16621965; 16386793; 22903728

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CFI gene.

• not provided (26 variants)
• Factor I deficiency;Atypical hemolytic-uremic syndrome with I factor anomaly;Age related macular degeneration 13 (2 variants)
• Atypical hemolytic-uremic syndrome (2 variants)
• Factor I deficiency (2 variants)
• CFI-related disorder (1 variants)
• Atypical hemolytic-uremic syndrome with I factor anomaly (1 variants)
• Age related macular degeneration 13;Atypical hemolytic-uremic syndrome with I factor anomaly;Factor I deficiency (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CFI gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	79	2	82
missense	2	4	198	15	3	222
nonsense	8	7	1			16
start loss			1			1
frameshift	17	3	2			22
inframe indel			3			3
splice donor/acceptor (+/-2bp)	1	7				8
splice region			13	19	2	34
non coding			4	31	34	69
Total	28	21	210	125	39

Highest pathogenic variant AF is 0.0000132

Variants in CFI

This is a list of pathogenic ClinVar variants found in the CFI region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-109740679-T-C		Atypical hemolytic-uremic syndrome with I factor anomaly	Benign (Nov 10, 2018)
4-109740749-A-G		Atypical hemolytic-uremic syndrome with I factor anomaly	Benign (Jan 13, 2018)
4-109740781-G-A		Atypical hemolytic-uremic syndrome with I factor anomaly • Factor I deficiency	Benign (Jul 22, 2021)
4-109740886-C-A		Atypical hemolytic-uremic syndrome with I factor anomaly • not specified	Benign (May 14, 2019)
4-109740895-A-G			Uncertain significance (Nov 13, 2023)
4-109740906-T-C			Uncertain significance (Aug 19, 2022)
4-109740912-A-G			Uncertain significance (Apr 28, 2023)
4-109740919-G-A			Likely benign (Jul 31, 2022)
4-109740925-C-CT			Uncertain significance (Jun 12, 2022)
4-109740929-A-G			Likely benign (Dec 21, 2023)
4-109740936-C-G		Atypical hemolytic-uremic syndrome with I factor anomaly • Age related macular degeneration 13;Atypical hemolytic-uremic syndrome with I factor anomaly;Factor I deficiency	Uncertain significance (Oct 14, 2022)
4-109740945-T-A			Uncertain significance (Dec 26, 2023)
4-109740953-A-T			Uncertain significance (Oct 13, 2022)
4-109740962-T-G		Atypical hemolytic-uremic syndrome with I factor anomaly	Uncertain significance (-)
4-109740984-T-A		Atypical hemolytic-uremic syndrome	Conflicting classifications of pathogenicity (Oct 14, 2023)
4-109740988-G-A		Atypical hemolytic-uremic syndrome with I factor anomaly • CFI-related disorder	Benign/Likely benign (Jan 22, 2024)
4-109740989-T-C		Age related macular degeneration 13;Atypical hemolytic-uremic syndrome with I factor anomaly;Factor I deficiency	Likely benign (Feb 26, 2022)
4-109740993-CCA-C			Likely pathogenic (Jul 27, 2020)
4-109740998-GT-G		CFI-related disorder	Likely pathogenic (Jan 26, 2022)
4-109741001-T-G			Uncertain significance (Jun 24, 2023)
4-109741002-T-C			Uncertain significance (Oct 17, 2023)
4-109741002-TC-T			Uncertain significance (Aug 17, 2023)
4-109741003-C-G		Atypical hemolytic-uremic syndrome with I factor anomaly • Atypical hemolytic-uremic syndrome • not specified	Conflicting classifications of pathogenicity (Jul 03, 2024)
4-109741007-C-T		Age related macular degeneration 13;Atypical hemolytic-uremic syndrome with I factor anomaly;Factor I deficiency	Likely pathogenic (Jun 30, 2021)
4-109741008-C-T		Atypical hemolytic-uremic syndrome with I factor anomaly	risk factor (Jun 01, 2004)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CFI	protein_coding	protein_coding	ENST00000394634	13	61484

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.54e-8	0.997	125667	0	81	125748	0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.201	298	308	0.968	0.0000158	3865
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000698	0.000698
Ashkenazi Jewish	0.000397	0.000397
East Asian	0.000217	0.000217
Finnish	0.00	0.00
European (Non-Finnish)	0.000317	0.000316
Middle Eastern	0.000217	0.000217
South Asian	0.000261	0.000261
Other	0.000982	0.000978

dbNSFP

Source: dbNSFP

• 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.
• Pathway: 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;Innate Immune System;Immune System;Regulation of Complement cascade;Complement cascade (Consensus)

Intolerance Scores

• loftool: 0.157
• rvis_EVS: 0.82
• rvis_percentile_EVS: 88.04

Haploinsufficiency Scores

• pHI: 0.0542
• hipred: N
• hipred_score: 0.273
• ghis: 0.392

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.502

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cfi
• Phenotype: renal/urinary system phenotype; hematopoietic system phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: cfi
• Affected structure: hyaloid vessel
• Phenotype tag: abnormal
• Phenotype quality: decreased diameter

Gene ontology

• Biological process: proteolysis;receptor-mediated endocytosis;complement activation, classical pathway;regulation of complement activation;innate immune response
• Cellular component: extracellular region;extracellular space;membrane;extracellular exosome
• Molecular function: serine-type endopeptidase activity;scavenger receptor activity;protein binding;metal ion binding