F2
protein-codingcoagulation factor II, thrombin, the group of Gla domain containing|Complement system regulators and receptors|Receptor ligands
Gene summary
This gene encodes the prothrombin protein (also known as coagulation factor II). This protein is proteolytically cleaved in multiple steps to form the activated serine protease thrombin. The activated thrombin enzyme plays an important role in thrombosis and hemostasis by converting fibrinogen to fibrin during blood clot formation, by stimulating platelet aggregation, and by activating additional coagulation factors. Thrombin also plays a role in cell proliferation, tissue repair, and angiogenesis as well as maintaining vascular integrity during development and postnatal life. Peptides derived from the C-terminus of this protein have antimicrobial activity against E. coli and P. aeruginosa. Mutations in this gene lead to various forms of thrombosis and dysprothrombinemia. Rapid increases in cytokine levels following coronavirus infections can dysregulate the coagulation cascade and produce thrombosis, compromised blood supply, and organ failure. [provided by RefSeq, May 2020]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013361
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008559
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008559
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0008559
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013361
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013361
Submitter: ClinGen
The relationship between F2 and congenital prothrombin deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. At least 15 causative variants in this gene are reported in humans, ranging from deletions, frameshift and missense variants. Congenital prothrombin deficiency is rare and is characterized by a bleeding diathesis due to reduced Factor II activity. Mutations in F2 were first associated with this disease in humans as early as 1992 by Iwahana et al and Morishita et al. (PMID: 1334372 & 1421398). Summary of Case Level Data (12 points): The association is seen in at least 9 probands in 8 publications (PMID: 1334372, 1421398, 12149217, 12492590, 6405779, 8839854, 7740448, 16543981). Variants segregated with disease in at least 8 additional family members. 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 biallelic loss of function. Summary of Experimental Data (5 points): Prothrombin is cleaved to yield thrombin that is essential to convert fibrin to fibrinogen for efficient clot formation. (PMID: 16006504). Mouse models that have the F2 gene knocked out show embryonic and perinatal lethality with massive hemorrhage and no clottable blood (PMID: 9636196, 9636195). In summary, the F2-Congenital prothrombin 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 June 24, 2020. (SOP Version 6)
Inheritance Pattern: AD
Disease ID:MONDO:0008559
Submitter: ClinGen
The F2 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to thrombin defect, using the ClinGen Clinical Validity Framework as of June, 2020. This association was made using case-level and case-control data. Prothrombin G20210A is a 3'UTR variant in the F2 gene that causes a gain of function and increased prothrombin synthesis. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense/regulatory region variants with similar gain of function impact are also reported. F2 was first associated with this disease in humans as early as 1996 (Poort et al., PMID: 8916933). Summary of Case Level Data (5.1 points): The association is seen in at least 7 probands in 7 publications (PMIDs: 8916933, 16988559, 27013614, 22716977, 23265743, 32194638, 11372696). Summary of Case-Control Data (9 points): Association between the prothrombin G20210A variant and thrombotic phenotype is seen in at least 4 case-control studies (PMID: 10027711, 29051591, 9669991, 8916933) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the G20210A as well as other variants observed causing resistance to inactivation by antithrombin and therefore causing an increased risk of thrombosis. (PMID: 8916933, 11443298, 15059842). Summary of Experimental Data (1 point): This gene-disease relationship is supported by functional assay that shows upregulation of mRNA 3' end processing (PMID: 11443298, 15059842). In summary, the F2- Thrombophilia due to thrombin defect 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 June 24, 2020 (SOP Version 6).
Inheritance Pattern: AR
Disease ID:MONDO:0013361
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013361
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.
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic; Pharmacogenomic
Rationale: In individuals with Thrombophilia due to thrombin defect , as relates to the specific 20210G-A variant, variant carriers may benefit from preventive measures and/or other interventions when other risk factors are present or in symptomatic disease; In AR forms of disease (Prothrombin deficiency), surveillance and prompt treatment of bleeding diatheses may reduce morbidity; Precautions should be taken related to certain agents that may provoke/worsen bleeding risk
Comments: Variants in F2 may interact with variants in other genes, such as F5, to result in susceptibility to hematologic manifestations; Heterozygous variants associated with Prothrombin deficiency have been described as demonstrating increased bleeding tendency, such as post-dental or surgical bleeding
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to F2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000506.5. 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 | 3 | 153 | 1 | 157 | ||
| missense | 11 | 17 | 112 | 9 | 149 | |
| nonsense | 4 | 3 | 7 | |||
| start loss | 0 | |||||
| frameshift | 4 | 2 | 1 | 7 | ||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 19 | 25 | 116 | 162 | 1 | 323 |
Highest pathogenic variant AF is 0.00015254434
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000497.1 | 14 | MANE Select | |
| Ensembl | ENSP00000308541.5 | 14 | MANE Select | |
| Ensembl | ENSP00000387413.1 | 8 | Standard | |
| Ensembl | ENSP00000433907.1 | 14 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Regulation of actin cytoskeleton - Homo sapiens (human)
- Neuroactive ligand-receptor interaction - Homo sapiens (human)
- Warfarin Pathway, Pharmacodynamics
- Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
Biological Process
- positive regulation of protein phosphorylation
- proteolysis
- endoplasmic reticulum to Golgi vesicle-mediated transport
- acute-phase response
- cell surface receptor signaling pathway
Molecular Function
- lipopolysaccharide binding
- serine-type endopeptidase activity
- signaling receptor binding
- calcium ion binding
- protein binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
- Golgi lumen
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000311907
- Coding exons
- 14
- Length
- 20327
- Individuals with no LoFs
- 125621
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 127
- Defined
- 125748
- p
- 0.000505
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.11 | 263 | 378 | 0.695 | 0.0000251 | 4041 |
| Missense (PolyPhen) | 71 | 151.31 | 0.46923 | 1594 | ||
| Synonymous | 0.713 | 143 | 154 | 0.927 | 0.0000107 | 1208 |
| Loss of Function | 3.74 | 12 | 36.3 | 0.331 | 0.00000208 | 373 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00014 | 0.00012 | rare |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00012 | 0.00011 | rare |
| Finnish | 0.00056 | 0.00055 | rare |
| European (Non-Finnish) | 0.00099 | 0.00092 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. {ECO:0000269|PubMed:2856554}.;
- Disease
- DISEASE: Factor II deficiency (FA2D) [MIM:613679]: A very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels. {ECO:0000269|PubMed:1349838, ECO:0000269|PubMed:1354985, ECO:0000269|PubMed:1421398, ECO:0000269|PubMed:14962227, ECO:0000269|PubMed:2719946, ECO:0000269|PubMed:3242619, ECO:0000269|PubMed:3567158, ECO:0000269|PubMed:3771562, ECO:0000269|PubMed:3801671, ECO:0000269|PubMed:6405779, ECO:0000269|PubMed:7792730, ECO:0000269|PubMed:7865694}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ischemic stroke (ISCHSTR) [MIM:601367]: A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. {ECO:0000269|PubMed:15534175}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Thrombophilia due to thrombin defect (THPH1) [MIM:188050]: A multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. {ECO:0000269|PubMed:2825773}. Note=The disease is caused by mutations affecting the gene represented in this entry. A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis.; DISEASE: Pregnancy loss, recurrent, 2 (RPRGL2) [MIM:614390]: A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. {ECO:0000269|PubMed:11506076}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.148
Intolerance Scores
- LoFtool
- 0.125
- RVIS EVS
- -0.71
- RVIS percentile EVS
- 14.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.955
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |