F5
protein-codingcoagulation factor V
Gene summary
This gene encodes an essential cofactor of the blood coagulation cascade. This factor circulates in plasma, and is converted to the active form by the release of the activation peptide by thrombin during coagulation. This generates a heavy chain and a light chain which are held together by calcium ions. The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin. Defects in this gene result in either an autosomal recessive hemorrhagic diathesis or an autosomal dominant form of thrombophilia, which is known as activated protein C resistance. [provided by RefSeq, Oct 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~74.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0008560
Submitter: ClinGen
The F5 gene has been associated with the Autosomal Dominant condition, Thrombophilia due to activated protein C resistance, using the ClinGen Clinical Validity Framework as of 08/14/2018. This association was made using case-level and case-control data. Factor V Leiden is a missense variant that causes the amino acid change Arg534Gln, which results in the loss of the APC cleavage site and, therefore, APC resistance. Individuals carrying this variant are at an increased risk of developing thrombosis and thromboembolism. Other missense variants with similar impact on APC resistance are also reported. F5 was first associated with this disease in humans as early as 1994 (Bertina et al., PMID: 8164741). Summary of Case Level Data (3.7 points): The association is seen in at least 16 probands in 6 publications (PMIDs: 28889200, 8164741, 7734374, 14617013, 27090446, 9454742). Variants in this gene segregated with disease in 6 additional family members. The Factor V Leiden variant has been reported in multiple publications from across the world. Summary of Case-Control Data (6.5 points): Association is seen in at least 3 case-control studies (PMID: 29179580, 11583312, 10666427, 26649017) at the single variant level. More case-control evidence is available in the literature. The mechanism for disease is gain of function, with the FVL variant and other missense variants observed causing resistance to inactivation by APC and therefore causing an increased risk of thrombosis. (PMID: 8164741). Summary of Experimental Data (4 points): This gene-disease relationship is supported by functional evidence and mouse models that recapitulate human disease (PMID: 16268462, 11110695, 9616155, 3286010). In summary, the F5- Thrombophilia due to activated protein C resistance 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 September 30, 2019 (SOP Version 6).
Inheritance Pattern: AD
Disease ID:MONDO:0008560
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0008560
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009210
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009210
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008560
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0011615
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009210
Submitter: ClinGen
The F5 gene has been associated with the Autosomal Recessive condition, Congenital Factor 5 Deficiency, using the ClinGen Clinical Validity Framework as of 08/29/2018. This association was made using case-level data only. Factor V deficiency, also called Parahemophilia, is rare and characterized by mild to severe bleeding diathesis. The disease was first described in 1947 by Owren et al. (PMID: 20293060). Factor V is essential for the activation of prothrombin and is a key component of the common pathway in the coagulation cascade. It has both procoagulant and anticoagulant properties and, thus, causes bleeding as well as thrombotic disorders. F5 mutations were first associated with congenital factor 5 deficiency in humans as early as 1998 (Guasch et al., PMID: 9576178). Summary of Case Level Data (12 points): The association is seen in at least 7 probands in 4 publications (PMIDs: 19486170, 9576178, 21777354, 18192108). Most of the reported variants are null or predicted null, including nonsense, frameshift and small deletions and insertions; however, a number of missense variants with functional evidence supporting their damaging effect are also reported. More genetic evidence is available in the literature, but the maximum allowable points for genetic evidence has been reached. The mechanism for disease is loss of function, with the majority of variants observed being null variants (frameshift/nonsense) and predicted or shown to result in reduced mRNA product due to nonsense-mediated decay (PMID: 9576178, 19486170). Summary of Experimental Data (4 points): This gene-disease relationship is supported by mouse models that recapitulate human disease and rescue of the disease phenotype (PMID: 8900278, 12855561, 10669158). The model system phenotype shows embryonic lethality for complete loss of FV activity, which indicates that non-lethal phenotype in humans may result due to residual activity of FV. In summary, the F5 – Congenital Factor V 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 March 25, 2020. (SOP Version 6)
Inheritance Pattern: AR
Disease ID:MONDO:0009210
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic; Pharmacogenomic
Rationale: In Thrombophilia due to activated protein C resistance, surveillance and treatment (including preventive measures in some individuals) may reduce morbidity; The condition may result in recurrent pregnancy loss, and awareness may help management of pregnancy; Precautions should be taken regarding the avoidance of certain medications (eg, estrogen-containing OCPs); Individuals with Factor V deficiency can suffer from bleeding diatheses of varying severity, and preventive measures, as well as prompt treatment (eg, with fresh frozen plasma or platelet transfusion in instances of severe bleeding) related to bleeding episodes can be beneficial
Comments: Variants in F5 may interact with variants in other genes, such as F2 and MTHFR, to result in susceptibility to hematologic manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to F5 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000130.5. 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 | 1 | 13 | 410 | 1 | 425 | |
| missense | 8 | 16 | 499 | 65 | 5 | 593 |
| nonsense | 26 | 14 | 1 | 1 | 42 | |
| start loss | 0 | |||||
| frameshift | 28 | 22 | 2 | 52 | ||
| splice donor/acceptor (+/-2bp) | 14 | 1 | 15 | |||
| Total | 62 | 67 | 516 | 475 | 7 | 1127 |
Highest pathogenic variant AF is 0.00012514963
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000121.2 | 25 | MANE Select | |
| Ensembl | ENSP00000356771.3 | 25 | MANE Select | |
| Ensembl | ENSP00000356770.3 | 25 | Standard | |
| Ensembl | ENSP00000356770.3 | 25 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Aminocaproic Acid Action Pathway
- Tranexamic Acid Action Pathway
- Urokinase Action Pathway
- Reteplase Action Pathway
Biological Process
- platelet degranulation
- endoplasmic reticulum to Golgi vesicle-mediated transport
- blood coagulation
- blood circulation
- post-translational protein modification
Molecular Function
- copper ion binding
- protein binding
Cellular Component
- Golgi membrane
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
- plasma membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000367797
- Coding exons
- 25
- Length
- 72423
- Individuals with no LoFs
- 125652
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 96
- Defined
- 125748
- p
- 0.000382
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.462 | 1085 | 1.13e+3 | 0.961 | 0.0000581 | 14744 |
| Missense (PolyPhen) | 313 | 396.97 | 0.78846 | 5279 | ||
| Synonymous | -0.178 | 411 | 406 | 1.01 | 0.0000214 | 4179 |
| Loss of Function | 5.12 | 41 | 94.7 | 0.433 | 0.00000500 | 1150 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00043 | 0.00043 | rare |
| Latino/Admixed American | 0.00035 | 0.00035 | rare |
| Ashkenazi Jewish | 0.00070 | 0.00069 | rare |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.00065 | 0.00065 | rare |
| European (Non-Finnish) | 0.00029 | 0.00029 | rare |
| South Asian | 0.00039 | 0.00039 | rare |
| Other | 0.00082 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Central regulator of hemostasis. It serves as a critical cofactor for the prothrombinase activity of factor Xa that results in the activation of prothrombin to thrombin.;
- Disease
- DISEASE: Factor V deficiency (FA5D) [MIM:227400]: A blood coagulation disorder leading to a hemorrhagic diathesis known as parahemophilia. {ECO:0000269|PubMed:10942390, ECO:0000269|PubMed:12393490}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Thrombophilia due to activated protein C resistance (THPH2) [MIM:188055]: A hemostatic disorder due to defective degradation of factor V by activated protein C. It is characterized by a poor anticoagulant response to activated protein C resulting in tendency to thrombosis. {ECO:0000269|PubMed:10391209, ECO:0000269|PubMed:10942390, ECO:0000269|PubMed:11435304, ECO:0000269|PubMed:11858490, ECO:0000269|PubMed:14617013, ECO:0000269|PubMed:14695241, ECO:0000269|PubMed:16710414, ECO:0000269|PubMed:8164741, ECO:0000269|PubMed:9454742}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Budd-Chiari syndrome (BDCHS) [MIM:600880]: A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera. {ECO:0000269|PubMed:9245936}. Note=Disease susceptibility is associated with variations 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: Pregnancy loss, recurrent, 1 (RPRGL1) [MIM:614389]: 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:11018168}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.0863
- RVIS EVS
- 3.23
- RVIS percentile EVS
- 99.38
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.551
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |