FCN3

protein-coding

ficolin 3, the group of Complement system activation components|Fibrinogen C domain containing

Gene summary

Ficolins are a group of proteins which consist of a collagen-like domain and a fibrinogen-like domain. In human serum, there are two types of ficolins, both of which have lectin activity. The protein encoded by this gene is a thermolabile beta-2-macroglycoprotein found in all human serum and is a member of the ficolin/opsonin p35 lectin family. The protein, which was initially identified based on its reactivity with sera from patients with systemic lupus erythematosus, has been shown to have a calcium-independent lectin activity. The protein can activate the complement pathway in association with MASPs and sMAP, thereby aiding in host defense through the activation of the lectin pathway. Alternative splicing occurs at this locus and two variants, each encoding a distinct isoform, have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003665.4

Inheritance

ClinVar variants

P:5U:60B:11

Top phenotype

Ficolin 3 deficiency

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:27,369,110-27,374,824

External References & Databases

Ensembl (ENSG00000142748)

Transcript & Mutation Effects

hg38 • Region Span ~5.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency due to ficolin3 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013467

Submitter: PanelApp Australia

immunodeficiency due to ficolin3 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013467

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Ficolin 3 deficiencyAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Sequelae have been described as including frequent and severe infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 19535802

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FCN3 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 60

not providedTotal: 18

Immunodeficiency due to ficolin3 deficiencyTotal: 12

FCN3-related disorderTotal: 6

MicrocephalyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003665.4. 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				6 clinvar		6
missense			54 clinvar	5 clinvar		59
nonsense						0
start loss						0
frameshift		5 clinvar	2 clinvar			7
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	5	60	11	0	76

Highest pathogenic variant AF is 0.00006574556

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003665.4	RefSeq	NP_003656.2	8	MANE Select
ENST00000270879.9	Ensembl	ENSP00000270879.4	8	MANE Select
NM_173452.3	RefSeq	NP_775628.1	7	Standard
ENST00000354982.2	Ensembl	ENSP00000347077.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Innate Immune System
Immune System
Initial triggering of complement
Ficolins bind to repetitive carbohydrate structures on the target cell surface
Lectin pathway of complement activation

Biological Process

complement activation, lectin pathway
proteolysis
complement activation
recognition of apoptotic cell
negative regulation of viral entry into host cell

Molecular Function

antigen binding
serine-type endopeptidase activity
protein binding
carbohydrate binding
metal ion binding

Cellular Component

extracellular region
collagen trimer
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000270879
Coding exons: 8
Length: 5713
Individuals with no LoFs: 125306
Homozygous LoFs: 2
Heterozygous LoFs: 426
Defined: 125734
p: 0.00170

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.422	162	178	0.911	0.0000106	1922
Missense (PolyPhen)		55	55.073	0.99867		653
Synonymous	1.67	50	67.4	0.742	0.00000383	598
Loss of Function	1.84	6	13.2	0.454	5.64e-7	149

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0038	0.0038	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00069	0.00069	rare
European (Non-Finnish)	0.0025	0.0025	notable
South Asian	0.00039	0.00039	rare
Other	0.0023	0.0023	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function in innate immunity through activation of the lectin complement pathway. Calcium-dependent and GlcNAc- binding lectin. Has affinity with GalNAc, GlcNAc, D-fucose, as mono/oligosaccharide and lipopolysaccharides from S.typhimurium and S.minnesota. {ECO:0000269|PubMed:11907111, ECO:0000269|PubMed:17215869}.;
Disease: DISEASE: Ficolin 3 deficiency (FCN3D) [MIM:613860]: A disorder characterized by immunodeficiency, recurrent infections, brain abscesses and recurrent warts on the fingers. Affected individuals have normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. {ECO:0000269|PubMed:19535802}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.600
RVIS EVS: 0.31
RVIS percentile EVS: 72.6

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.139

Gene Damage Prediction

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