FGA
protein-codingfibrinogen alpha chain, the group of Fibrinogen C domain containing|Receptor ligands
Gene summary
This gene encodes the alpha subunit of the coagulation factor fibrinogen, which is a component of the blood clot. Following vascular injury, the encoded preproprotein is proteolytically processed by thrombin during the conversion of fibrinogen to fibrin. Mutations in this gene lead to several disorders, including dysfibrinogenemia, hypofibrinogenemia, afibrinogenemia and renal amyloidosis. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that undergoes proteolytic processing. [provided by RefSeq, Jan 2016]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~7.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0019733
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007099
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007099
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014452
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008737
Submitter: Orphanet
Inheritance Pattern: SD
Disease ID:MONDO:0018060
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0002305
Submitter: Genomics England PanelApp
Inheritance Pattern: SD
Disease ID:MONDO:0018060
Submitter: ClinGen
The relationship between FGA and congenital fibrinogen deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. More than a 30 pathogenic variants in this gene are reported in humans, ranging from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital fibrinogen deficiency is characterized by quantitative and qualitative defects in fibrinogen. It may manifest as afibrinogenemia, dysfibrinogenemia and hypodysfibrinogenemia. Clinical symptoms include a bleeding diathesis and/or a thrombotic phenotype. Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 6 publications (PMID:11460510, 11739173, 11354637, 10602365, 11159525, 14615374). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism for disease have been reported to be heterozygous as well as biallelic loss of function. (PMID: 10602365, 11460510). Summary of Experimental Data (6 points): FGA encodes the α subunit of the coagulation factor, fibrinogen, which is a hexamer of three subunit chains (PMID: 22836683). The Aα fibrinopeptide interacts with thrombin, which catalyzes the conversion of fibrinogen to fibrin (PMID: 15572239). It is synthesized in the liver and secreted into the plasma (PMID: 20921339). Mouse and zebrafish models are reported that recapitulate fibrinogen deficiency (PMID: 7649481, 24553182). In summary, the FGA-Congenital fibrinogen deficiency gene-disease relationship is definitive. 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 Hemostasis/Thrombosis GCEP on January 22, 2020 (SOP Version 7). Lumping & Splitting information: OMIM assertions - (1) Congenital Afibrinogenemia (MIM: 202400); (2) Congenital Dysfibrinogenemia (MIM: 616004); (3) Congenital Hypodysfibrinogenemia (MIM: 616004); (4) Familial Visceral Amyloidosis (MIM: 105200). Orphanet assertions - (1) Familial afibrinogenemia; (2) Familial dysfibrinogenemia; (3) Familial hypodysfibrinogenemia; (4) Familial hypofibrinogenemia; (5) AFib amyloidosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) underlying the disease entities: Congenital Afibrinogenemia, Congenital Dysfibrinogenemia, Congenital Hypodysfibrinogenemia and Familial hypofibrinogenemia. These entities have been lumped together under Congenital Fibrinogen Deficiency. Familial Visceral Amyloidosis is split out from this larger entity. It does not fall under the purview of the Hemostasis/Thrombosis GCEP, and this entity will be curated separately in the future.
Inheritance Pattern: AR
Disease ID:MONDO:0008737
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014452
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0002305
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008737
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014452
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0015096
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007099
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Gastrointestinal; Hematologic; Musculoskeletal; Renal
Intervention: Cardiovascular; Gastrointestinal; Hematologic; Pharmacogenomic
Rationale: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FGA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021871.4. 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 | 7 | 27 | 34 | |||
| missense | 4 | 11 | 177 | 16 | 1 | 209 |
| nonsense | 7 | 6 | 3 | 16 | ||
| start loss | 0 | |||||
| frameshift | 8 | 18 | 2 | 28 | ||
| splice donor/acceptor (+/-2bp) | 1 | 5 | 2 | 8 | ||
| Total | 20 | 40 | 191 | 43 | 1 | 295 |
Highest pathogenic variant AF is 0.00011464834
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_068657.1 | 5 | MANE Select | |
| Ensembl | ENSP00000385981.3 | 5 | MANE Select | |
| RefSeq | NP_000499.1 | 6 | Standard | |
| Ensembl | ENSP00000498441.1 | 6 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- 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
Biological Process
- toll-like receptor signaling pathway
- adaptive immune response
- platelet degranulation
- cell-matrix adhesion
- blood coagulation
Molecular Function
- signaling receptor binding
- structural molecule activity
- extracellular matrix structural constituent
- protein binding
- metal ion binding
Cellular Component
- extracellular region
- fibrinogen complex
- extracellular space
- endoplasmic reticulum lumen
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000302053
- Coding exons
- 6
- Length
- 7641
- Individuals with no LoFs
- 125610
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 136
- Defined
- 125746
- p
- 0.000541
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.670 | 498 | 458 | 1.09 | 0.0000252 | 5688 |
| Missense (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 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00032 | 0.00031 | rare |
| Latino/Admixed American | 0.00067 | 0.00067 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00068 | 0.00068 | rare |
| South Asian | 0.00062 | 0.00062 | rare |
| Other | 0.00098 | 0.00098 | rare |
dbNSFP Gene Annotations
Source:
- 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.;
Recessive Scores
- pRec
- 0.417
Intolerance Scores
- LoFtool
- 0.356
- RVIS EVS
- -0.75
- RVIS percentile EVS
- 13.71
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.423
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |