FGA

fibrinogen alpha chain, the group of Fibrinogen C domain containing|Receptor ligands

Basic information

Region (hg38): 4:154583126-154590742

Links

ENSG00000171560 ∙ NCBI:2243 ∙ OMIM:134820 ∙ HGNC:3661 ∙ Uniprot:P02671 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• thrombophilia (Strong), mode of inheritance: AD
• thrombophilia (Strong), mode of inheritance: AR
• familial dysfibrinogenemia (Definitive), mode of inheritance: AD
• congenital afibrinogenemia (Definitive), mode of inheritance: AR
• familial visceral amyloidosis (Moderate), mode of inheritance: AD
• AFib amyloidosis (Supportive), mode of inheritance: AD
• congenital afibrinogenemia (Supportive), mode of inheritance: AR
• familial dysfibrinogenemia (Supportive), mode of inheritance: AD
• familial hypofibrinogenemia (Supportive), mode of inheritance: AD
• familial visceral amyloidosis (Strong), mode of inheritance: AD
• congenital afibrinogenemia (Strong), mode of inheritance: AR
• familial dysfibrinogenemia (Strong), mode of inheritance: AD
• congenital fibrinogen deficiency (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Afibrinogenemia, congenital; Dysfibrinogenemia, congenital; Amyloidosis, hereditary, systemic 2	AD/AR	Cardiovascular; Gastrointestinal; Hematologic; Pharmacogenomic	Individuals with afibrinogenemia/dysfibrinogenemia are at risk of a variety of bleeding diatheses; Preventive or treatment-based (eg, with fibrinogen in the case of congenital afibrinogenemia) measures may be beneficial; Individuals with Hereditary amyloidosis may be at risk of cardiovascular complications, including arrhythmia, and surveillance may allow prompt detection and management; The treatment of amyloidosis differs depending on the genetic cause (genetic diagnosis may additionally help avoid relatively high-risk treatment regimens), and in fibrinogen-related amyloidosis, liver transplantation may be beneficial	Cardiovascular; Gastrointestinal; Hematologic; Musculoskeletal; Renal	5645286; 7298640; 6191801; 4052020; 3726812; 3618591; 3590111; 3345340; 2133234; 1675636; 2070049; 1391954; 1634621; 8097946; 8140431; 8473507; 8113408; 8675656; 8639778; 9389696; 9916133; 10891444; 10910940; 11739173; 11159525; 12050338; 12358944; 14615374; 15489905; 16362348; 18500534; 20806111; 21245743; 22732251; 22795623

ClinVar

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

• not provided (9 variants)
• Hypofibrinogenemia (5 variants)
• Familial dysfibrinogenemia (3 variants)
• Congenital afibrinogenemia (3 variants)
• FGA-related disorder (3 variants)
• Congenital afibrinogenemia;Familial dysfibrinogenemia;Familial visceral amyloidosis, Ostertag type (2 variants)
• Dysfibrinogenemia (2 variants)
• Familial dysfibrinogenemia;Familial visceral amyloidosis, Ostertag type;Congenital afibrinogenemia (1 variants)
• Familial visceral amyloidosis, Ostertag type (1 variants)
• Abnormal bleeding (1 variants)
• Familial visceral amyloidosis, Ostertag type;Familial dysfibrinogenemia;Congenital afibrinogenemia (1 variants)
• Familial hypodysfibrinogenemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FGA 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			3	14	1	18
missense	6	5	80	7	1	99
nonsense	3	3	4			10
start loss						0
frameshift	5	10	1		1	17
inframe indel						0
splice donor/acceptor (+/-2bp)	1	2				3
splice region			1			1
non coding				2	14	16
Total	15	20	88	23	17

Highest pathogenic variant AF is 0.0000789

Variants in FGA

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

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

Position	Type	Phenotype	Significance	ClinVar
4-154583796-G-A			Benign (Nov 11, 2018)
4-154584089-A-AGAAGACAGAGTGCTCCCATTCCCACTTC		not specified	Benign (May 12, 2021)
4-154584137-AG-A		Familial visceral amyloidosis, Ostertag type	Benign (May 28, 2019)
4-154584139-G-A		not specified	Benign (May 24, 2021)
4-154584180-C-A		FGA-related disorder	Uncertain significance (Aug 30, 2023)
4-154584198-A-G		Congenital afibrinogenemia	Uncertain significance (Apr 28, 2021)
4-154584233-T-C		Inborn genetic diseases	Uncertain significance (Jan 10, 2022)
4-154584282-CTGCTTGGCAGTT-C		Hepatocellular carcinoma	Pathogenic (Jun 15, 2021)
4-154584286-T-G		Inborn genetic diseases	Uncertain significance (Feb 21, 2024)
4-154584291-A-G			Uncertain significance (Sep 16, 2018)
4-154584311-C-G			Uncertain significance (Nov 08, 2019)
4-154584332-T-G		Inborn genetic diseases	Uncertain significance (Dec 16, 2023)
4-154584353-T-A		Congenital afibrinogenemia	Uncertain significance (Apr 28, 2021)
4-154584375-G-A		Familial visceral amyloidosis, Ostertag type • Familial visceral amyloidosis, Ostertag type;Familial dysfibrinogenemia;Congenital afibrinogenemia	Uncertain significance (Aug 30, 2021)
4-154584385-G-T		Inborn genetic diseases	Uncertain significance (Oct 26, 2021)
4-154584402-C-T		Inborn genetic diseases	Likely benign (Jun 27, 2022)
4-154584411-C-T		Inborn genetic diseases	Uncertain significance (Jul 12, 2023)
4-154584432-C-T		Inborn genetic diseases	Uncertain significance (Jan 23, 2023)
4-154584481-A-G			Likely benign (Sep 22, 2017)
4-154584491-C-T		FGA-related disorder	Uncertain significance (Jun 24, 2024)
4-154584539-T-G		FGA-related disorder	Uncertain significance (Mar 09, 2023)
4-154584540-C-G		FGA-related disorder	Likely benign (Dec 04, 2023)
4-154584548-A-G		Inborn genetic diseases	Uncertain significance (Jan 17, 2024)
4-154584566-C-G		Inborn genetic diseases	Uncertain significance (Dec 01, 2022)
4-154584569-TG-T		Congenital afibrinogenemia	Pathogenic (Apr 28, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FGA	protein_coding	protein_coding	ENST00000302053	6	7641

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.22e-13	0.486	125610	0	136	125746	0.000541

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.670	498	458	1.09	0.0000252	5688
Missense in Polyphen		108	118.02	0.91514		1574
Synonymous	-1.12	189	170	1.11	0.00000987	1702
Loss of Function	1.46	25	34.2	0.731	0.00000199	402

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000980	0.000973
Ashkenazi Jewish	0.00	0.00
East Asian	0.000326	0.000326
Finnish	0.00	0.00
European (Non-Finnish)	0.000680	0.000677
Middle Eastern	0.000326	0.000326
South Asian	0.000621	0.000621
Other	0.000982	0.000978

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Cleaved by the protease thrombin to yield monomers which, together with fibrinogen beta (FGB) and fibrinogen gamma (FGG), polymerize to form an insoluble fibrin matrix. Fibrin has a major function in hemostasis as one of the primary components of blood clots. In addition, functions during the early stages of wound repair to stabilize the lesion and guide cell migration during re-epithelialization. Was originally thought to be essential for platelet aggregation, based on in vitro studies using anticoagulated blood. However, subsequent studies have shown that it is not absolutely required for thrombus formation in vivo. Enhances expression of SELP in activated platelets via an ITGB3- dependent pathway. Maternal fibrinogen is essential for successful pregnancy. Fibrin deposition is also associated with infection, where it protects against IFNG-mediated hemorrhage. May also facilitate the immune response via both innate and T-cell mediated pathways. {ECO:0000250|UniProtKB:E9PV24}.
• Disease: DISEASE: Congenital afibrinogenemia (CAFBN) [MIM:202400]: Rare autosomal recessive disorder is characterized by bleeding that varies from mild to severe and by complete absence or extremely low levels of plasma and platelet fibrinogen. {ECO:0000269|PubMed:25427968}. Note=The disease is caused by mutations affecting the gene represented in this entry. The majority of cases of afibrinogenemia are due to truncating mutations. Variations in position Arg-35 (the site of cleavage of fibrinopeptide a by thrombin) leads to alpha-dysfibrinogenemias.; DISEASE: Amyloidosis 8 (AMYL8) [MIM:105200]: A form of hereditary generalized amyloidosis. Clinical features include extensive visceral amyloid deposits, renal amyloidosis resulting in nephrotic syndrome, arterial hypertension, hepatosplenomegaly, cholestasis, petechial skin rash. There is no involvement of the nervous system. {ECO:0000269|PubMed:8097946}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dysfibrinogenemia, congenital (DYSFIBRIN) [MIM:616004]: A disorder characterized by qualitative abnormalities (dysfibrinogenemia) of the circulating fibrinogen. Affected individuals are frequently asymptomatic, but some patients have bleeding diathesis, thromboembolic complications, or both. In some cases, dysfibrinogenemia is associated with low circulating fibrinogen levels (hypodysfibrinogenemia). {ECO:0000269|PubMed:16846481, ECO:0000269|PubMed:8473507}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Platelet activation - Homo sapiens (human);Platelet Aggregation Inhibitor Pathway, Pharmacodynamics;Aminocaproic Acid Action Pathway;Tranexamic Acid Action Pathway;Urokinase Action Pathway;Reteplase Action Pathway;Streptokinase Action Pathway;Tenecteplase Action Pathway;Alteplase Action Pathway;Anistreplase Action Pathway;Aprotinin Action Pathway;Phenindione Action Pathway;Dicoumarol Action Pathway;Warfarin Action Pathway;Acenocoumarol Action Pathway;Coagulation ;Bivalirudin Action Pathway;Argatroban Action Pathway;Ardeparin Action Pathway;Heparin Action Pathway;Fondaparinux Action Pathway;Enoxaparin Action Pathway;Phenprocoumon Action Pathway;Dicumarol Action Pathway;Ximelagatran Action Pathway;Lepirudin Action Pathway;Blood Clotting Cascade;Human Complement System;VEGFA-VEGFR2 Signaling Pathway;Dengue-2 Interactions with Blood Clotting Cascade;MAP2K and MAPK activation;Disease;Signal Transduction;fibrinolysis pathway;intrinsic prothrombin activation pathway;Post-translational protein phosphorylation;Integrin cell surface interactions;Toll-Like Receptors Cascades;Post-translational protein modification;Metabolism of proteins;Extracellular matrix organization;GRB2:SOS provides linkage to MAPK signaling for Integrins ;p130Cas linkage to MAPK signaling for integrins;Integrin alphaIIb beta3 signaling;Innate Immune System;Immune System;Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs);Platelet Aggregation (Plug Formation);Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Beta3 integrin cell surface interactions;Integrin signaling;Hemostasis;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Common Pathway of Fibrin Clot Formation;Formation of Fibrin Clot (Clotting Cascade);Regulation of TLR by endogenous ligand;Signaling by RAS mutants;Signaling by high-kinase activity BRAF mutants;Signaling by moderate kinase activity BRAF mutants;Paradoxical activation of RAF signaling by kinase inactive BRAF;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction;Beta1 integrin cell surface interactions;Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling;Beta2 integrin cell surface interactions;extrinsic prothrombin activation pathway (Consensus)

Recessive Scores

• pRec: 0.417

Intolerance Scores

• loftool: 0.356
• rvis_EVS: -0.75
• rvis_percentile_EVS: 13.71

Haploinsufficiency Scores

• pHI: 0.224
• hipred: N
• hipred_score: 0.214
• ghis: 0.665

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.423

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fga
• Phenotype: reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; embryo phenotype; liver/biliary system phenotype; immune system phenotype; skeleton phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: toll-like receptor signaling pathway;adaptive immune response;platelet degranulation;cell-matrix adhesion;blood coagulation;extracellular matrix organization;plasminogen activation;positive regulation of heterotypic cell-cell adhesion;cellular protein-containing complex assembly;fibrinolysis;induction of bacterial agglutination;post-translational protein modification;cellular protein metabolic process;innate immune response;positive regulation of vasoconstriction;positive regulation of exocytosis;positive regulation of protein secretion;protein polymerization;response to calcium ion;protein-containing complex assembly;positive regulation of ERK1 and ERK2 cascade;platelet aggregation;blood coagulation, common pathway;blood coagulation, fibrin clot formation;positive regulation of peptide hormone secretion;positive regulation of substrate adhesion-dependent cell spreading;negative regulation of extrinsic apoptotic signaling pathway via death domain receptors;negative regulation of endothelial cell apoptotic process
• Cellular component: extracellular region;fibrinogen complex;extracellular space;endoplasmic reticulum lumen;plasma membrane;cell cortex;external side of plasma membrane;cell surface;platelet alpha granule;platelet alpha granule lumen;synapse;collagen-containing extracellular matrix;extracellular exosome;blood microparticle;extracellular vesicle
• Molecular function: signaling receptor binding;structural molecule activity;extracellular matrix structural constituent;protein binding;metal ion binding;cell adhesion molecule binding