F12
protein-codingcoagulation factor XII
Gene summary
This gene encodes coagulation factor XII which circulates in blood as a zymogen. This single chain zymogen is converted to a two-chain serine protease with an heavy chain (alpha-factor XIIa) and a light chain. The heavy chain contains two fibronectin-type domains, two epidermal growth factor (EGF)-like domains, a kringle domain and a proline-rich domain, whereas the light chain contains only a catalytic domain. On activation, further cleavages takes place in the heavy chain, resulting in the production of beta-factor XIIa light chain and the alpha-factor XIIa light chain becomes beta-factor XIIa heavy chain. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then to beta-factor XIIa. The active factor XIIa participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. It activates coagulation factors VII and XI. Defects in this gene do not cause any clinical symptoms and the sole effect is that whole-blood clotting time is prolonged. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~14.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0012526
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009315
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012526
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009315
Submitter: ClinGen
The relationship between F12 and congenital factor XII deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of January, 2020. This association was made using case-level and experimental data. Pathogenic variants in this gene reported in humans range from partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XII deficiency does not manifest as overt clinical symptoms and is diagnosed as an incidental finding when patients are tested for other reasons. Studies indicate that FXII deficiency neither predisposes to venous thromboembolism nor protects against it (PMID: 25696836, 15306750). Nevertheless, mutations in F12 result in reduced activity with or without reduced antigen levels of FXII. Mutations in F12 were first associated with this disease in humans as early as 1987 by Bernardi et al. (PMID: 2882793); however, the molecular defect was reported by Miyata et al in 1989 (PMID: 2510163). Summary of Case Level Data (12 points): The association is seen in at least 11 probands in 8 publications (PMID: 29383625, 20022356, 18024408, 20386432, 26709783, 21264442, 28007010, 15205584). 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 is expected to be biallelic loss of function, with heterozygous individuals usually having intermediate levels of factor activity. Summary of Experimental Data (4 points): FXII is the first component of the intrinsic pathway of the coagulation cascade and activates FXI (PMID: 30700128). The significance of FXII in the coagulation pathway is not clear, however. Mouse models are reported that recapitulate FXII deficiency, without any clinical manifestations, suggesting that FXII deficiency does not affect hemostasis in vivo (PMID: 15351846). This is similar to what is observed in humans. In cats, FXII deficiency is a naturally occurring defect and leads to complete lack of FXII activity and antigen (PMID: 31022435). In summary, the F12-Congenital FXII 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) Angioedema, hereditary, type III (MIM: 610618); (2) Factor XII deficiency (MIM: 234000). Orphanet assertions - (1) F12-related hereditary angioedema with normal C1Inh; (2) Congenital factor XII deficiency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the phenotype, inheritance pattern and molecular mechanism underlying the two disease entities to be different and hence the association of F12 with each entity was evaluated separately.
Inheritance Pattern: AD
Disease ID:MONDO:0012526
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0012526
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012526
Submitter: ClinGen
The relationship between *F12* and Hereditary Angioedema type III (HAE-III) inherited in the autosomal dominant pattern has been evaluated using the ClinGen Clinical Validity Framework as of May, 2022. This association was made using case-level and experimental data. HAE-III is characterized by recurrent skin swelling and abdominal pain attacks and differs from types I and II in that the concentration and function of C1-esterase inhibitor is normal. Specific heterozygous missense variants in the proline-rich domain of F12 cause HAE-III. Mutations in F12 were first associated with this disease in humans in 2006 by Cichon et al. (PMID: 17186468) and Dewald et al (PMID: 16638441). Summary of Case Level Data (6.3 points): The association is seen in at least 31 probands in 6 publications (PMID: 26193639, 16638441, 17381464, 21849258, 25952149, 36203598). The recurrent founder variant, Thr328Lys (also known as Thr309Lys), is reported in the majority of individuals with HAE-III. This variant segregated with disease in at least 42 additional family members. It appears that only variation at the Thr328 residue may result in the HAE-III phenotype, with other reported variants of Thr328Arg and a deletion that includes Thr328. The mechanism for disease is expected to be heterozygous gain of function. Summary of Experimental Data (6 points): *F12* is involved in the kallikrein-kinin cascade that results in the generation of braydkinin. Due to gain of function mutations in *F12*, excessive bradykinin is generated which results in increased vascular permeability (PMID: 30463937). Functional data in plasma samples from HAE-FXIIThr309Lys patients and in transfected cell lines provide further support for non-canonical cleavage and activation of FXIIThr309Lys by thrombin as the cause of HAE (López-Gálvez R, et al., 2021, PMID: 33725261). An HAE-III transgenic mouse model with human-derived Thr328Lys variant recapitulates the human phenotype (PMID: 26193639). In summary, there is definitive evidence supporting the relationship between *F12* and autosomal dominant Hereditary Angioedema type III. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the HT GCEP on 01/23/2020. It was reevaluated on 05/25/2022 and 06/03/2024. As a result of the most recent reevaluation, with the addition of 24 probands (PMIDs: 25952149, 36203598) the classificaiton increased from Moderate to Definitive. Lumping & Splitting information: OMIM assertions - (1) Angioedema, hereditary, type III (MIM: 610618); (2) Factor XII deficiency (MIM: 234000). Orphanet assertions - (1) F12-related hereditary angioedema with normal C1Inh; (2) Congenital factor XII deficiency. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the phenotype, inheritance pattern and molecular mechanism underlying the two disease entities to be different and hence the association of *F12* with each entity was evaluated separately.
Inheritance Pattern: AD
Disease ID:MONDO:0012526
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009315
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Hematologic
Intervention: Allergy/Immunology/Infectious; Pharmacogenomic
Rationale: In Hereditary angioedema, attacks, which can include potentially life-threatening upper airway obstruction, can be precipitated by high estrogen levels (eg, pregnancy, OCPs)
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to F12 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000505.4. 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 | 11 | 47 | 58 | |||
| missense | 3 | 3 | 100 | 18 | 1 | 125 |
| nonsense | 5 | 5 | ||||
| start loss | 0 | |||||
| frameshift | 3 | 2 | 2 | 7 | ||
| splice donor/acceptor (+/-2bp) | 2 | 5 | 3 | 10 | ||
| Total | 8 | 15 | 116 | 65 | 1 | 205 |
Highest pathogenic variant AF is 0.00034025856
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000496.2 | 14 | MANE Select | |
| Ensembl | ENSP00000253496.3 | 14 | MANE Select | |
| Ensembl | ENSP00000512476.1 | 5 | Standard | |
| Ensembl | ENSP00000512477.1 | 3 | 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
- plasma kallikrein-kinin cascade
- Factor XII activation
- proteolysis
- blood coagulation, intrinsic pathway
- positive regulation of plasminogen activation
Molecular Function
- serine-type endopeptidase activity
- calcium ion binding
- protein binding
- misfolded protein binding
Cellular Component
- extracellular region
- extracellular space
- rough endoplasmic reticulum
- plasma membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000253496
- Coding exons
- 14
- Length
- 7437
- Individuals with no LoFs
- 125599
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 147
- Defined
- 125746
- p
- 0.000585
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.924 | 307 | 356 | 0.862 | 0.0000185 | 3891 |
| Missense (PolyPhen) | 114 | 138.09 | 0.82556 | 1607 | ||
| Synonymous | 0.481 | 147 | 155 | 0.951 | 0.00000803 | 1229 |
| Loss of Function | 2.57 | 17 | 32.9 | 0.517 | 0.00000153 | 355 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00019 | 0.00018 | rare |
| Latino/Admixed American | 0.00024 | 0.00023 | rare |
| Ashkenazi Jewish | 0.0045 | 0.0043 | notable |
| East Asian | 0.00067 | 0.00065 | rare |
| Finnish | 0.00015 | 0.000092 | rare |
| European (Non-Finnish) | 0.00059 | 0.00054 | rare |
| South Asian | 0.00051 | 0.00049 | rare |
| Other | 0.00050 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta- factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa. {ECO:0000269|PubMed:21304106}.;
- Disease
- DISEASE: Factor XII deficiency (FA12D) [MIM:234000]: An asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. Factor XII deficiency is divided into two categories, a cross-reacting material (CRM)- negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection). {ECO:0000269|PubMed:10361128, ECO:0000269|PubMed:11776307, ECO:0000269|PubMed:15205584, ECO:0000269|PubMed:15617741, ECO:0000269|PubMed:2510163, ECO:0000269|PubMed:2882793, ECO:0000269|PubMed:8049433, ECO:0000269|PubMed:8528215, ECO:0000269|PubMed:9354665}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hereditary angioedema 3 (HAE3) [MIM:610618]: An hereditary angioedema occurring only in women. Hereditary angioedema is an autosomal dominant disorder characterized by episodic local swelling involving subcutaneous or submucous tissue of the upper respiratory and gastrointestinal tracts, face, extremities, and genitalia. Hereditary angioedema type 3 differs from types 1 and 2 in that both concentration and function of C1 esterase inhibitor are normal. Hereditary angioedema type 3 is precipitated or worsened by high estrogen levels (e.g., during pregnancy or treatment with oral contraceptives). {ECO:0000269|PubMed:16638441, ECO:0000269|PubMed:17186468}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.0955
Intolerance Scores
- LoFtool
- 0.323
- RVIS EVS
- 0.53
- RVIS percentile EVS
- 80.96
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.528
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |