F12

coagulation factor XII

Basic information

Region (hg38): 5:177402132-177416583

Links

ENSG00000131187 ∙ NCBI:2161 ∙ OMIM:610619 ∙ HGNC:3530 ∙ Uniprot:P00748 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary angioedema type 3 (Strong), mode of inheritance: AD
• congenital factor XII deficiency (Supportive), mode of inheritance: AR
• hereditary angioedema type 3 (Supportive), mode of inheritance: AD
• hereditary angioedema type 3 (Definitive), mode of inheritance: AD
• congenital factor XII deficiency (Definitive), mode of inheritance: AR
• hereditary angioedema type 3 (Moderate), mode of inheritance: AD
• hereditary angioedema type 3 (Strong), mode of inheritance: AD
• congenital factor XII deficiency (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Angioedema, hereditary, 3	AD/AR	Allergy/Immunology/Infectious; Pharmacogenomic	In Hereditary angioedema, attacks, which can include potentially life-threatening upper airway obstruction, can be precipitated by high estrogen levels (eg, pregnancy, OCPs)	Allergy/Immunology/Infectious; Hematologic	14490552; 4968868; 5432188; 6348471; 2882793; 2110579; 1905067; 8419231; 7947293; 11069485; 15306750; 15013868; 15678272; 19477491; 20729721; 20667118; 20695852; 21849258; 20729721; 21297451; 22043782; 22801442; 22197449; 22729959

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the F12 gene.

• not provided (68 variants)
• Hereditary angioedema type 3 (49 variants)
• Factor XII deficiency disease (46 variants)
• Inborn genetic diseases (18 variants)
• Hereditary angioneurotic edema (6 variants)
• Nephrolithiasis/osteoporosis, hypophosphatemic (5 variants)
• not specified (4 variants)
• Factor XII deficiency disease;Hereditary angioedema type 3 (3 variants)
• F12-related condition (2 variants)
• Thrombus (1 variants)
• F12-Related Disorders (1 variants)
• FACTOR XII POLYMORPHISM (1 variants)
• Urticaria;Hypertensive disorder;Hyperbilirubinemia;Angioedema (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the F12 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			7	13	3	23
missense	2		32	6	2	42
nonsense		2				2
start loss						0
frameshift		1	2			3
inframe indel						0
splice donor/acceptor (+/-2bp)		2				2
splice region			2	3	1	6
non coding			5	5	14	24
Total	2	5	46	24	19

Highest pathogenic variant AF is 0.0000197

Variants in F12

This is a list of pathogenic ClinVar variants found in the F12 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-177402206-G-A		Factor XII deficiency disease • Hereditary angioedema type 3	Uncertain significance (Mar 30, 2018)
5-177402283-C-T		Hereditary angioedema type 3 • Factor XII deficiency disease	Uncertain significance (Jan 13, 2018)
5-177402327-A-G		Inborn genetic diseases	Uncertain significance (Feb 22, 2023)
5-177402328-G-A			Likely benign (Jan 11, 2024)
5-177402349-G-T			Likely benign (May 16, 2023)
5-177402361-G-A			Likely benign (Nov 13, 2022)
5-177402366-C-T			Uncertain significance (Feb 01, 2024)
5-177402372-A-C		Hereditary angioedema type 3	Uncertain significance (-)
5-177402372-A-T		FACTOR XII (WASHINGTON D.C.)	Pathogenic (Nov 01, 1989)
5-177402404-G-A			Likely benign (Oct 14, 2023)
5-177402436-C-T		Factor XII deficiency disease • Hereditary angioedema type 3	Conflicting classifications of pathogenicity (Jan 13, 2018)
5-177402442-CG-C		not specified	Uncertain significance (Dec 18, 2023)
5-177402460-C-T		Factor XII deficiency disease • F12-related disorder	Conflicting classifications of pathogenicity (Oct 03, 2023)
5-177402466-C-T			Likely benign (Aug 19, 2022)
5-177402561-CG-C			Uncertain significance (Jul 14, 2021)
5-177402596-C-T		Inborn genetic diseases	Uncertain significance (Dec 02, 2022)
5-177402609-A-C			Uncertain significance (Oct 01, 2023)
5-177402631-T-C		Hereditary angioedema type 3	Uncertain significance (-)
5-177402656-G-C		Inborn genetic diseases	Uncertain significance (Dec 20, 2023)
5-177402659-AC-A		Factor XII deficiency disease	Pathogenic (Jan 06, 2023)
5-177402661-C-T			Likely benign (Oct 01, 2023)
5-177402670-C-T			Likely benign (May 01, 2023)
5-177402677-A-G		Inborn genetic diseases	Uncertain significance (Jan 23, 2024)
5-177402702-C-A			Likely benign (Nov 28, 2023)
5-177403242-A-G			Benign (Nov 11, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
F12	protein_coding	protein_coding	ENST00000253496	14	7437

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.25e-8	0.996	125599	0	147	125746	0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.924	307	356	0.862	0.0000185	3891
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000435	0.000427
Ashkenazi Jewish	0.00446	0.00428
East Asian	0.000670	0.000653
Finnish	0.000146	0.0000924
European (Non-Finnish)	0.000591	0.000536
Middle Eastern	0.000670	0.000653
South Asian	0.000507	0.000490
Other	0.000503	0.000489

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);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;Dengue-2 Interactions with Complement and Coagulation Cascades;Dengue-2 Interactions with Blood Clotting Cascade;Complement and Coagulation Cascades;intrinsic prothrombin activation pathway;Intrinsic Pathway of Fibrin Clot Formation;Hemostasis;Formation of Fibrin Clot (Clotting Cascade) (Consensus)

Recessive Scores

• pRec: 0.0955

Intolerance Scores

• loftool: 0.323
• rvis_EVS: 0.53
• rvis_percentile_EVS: 80.96

Haploinsufficiency Scores

• pHI: 0.287
• hipred: N
• hipred_score: 0.274
• ghis: 0.446

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.528

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: F12
• 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); normal phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: plasma kallikrein-kinin cascade;Factor XII activation;proteolysis;blood coagulation, intrinsic pathway;positive regulation of plasminogen activation;protein processing;protein autoprocessing;positive regulation of blood coagulation;zymogen activation;fibrinolysis;innate immune response;response to misfolded protein;positive regulation of fibrinolysis
• Cellular component: extracellular region;extracellular space;rough endoplasmic reticulum;plasma membrane;extracellular exosome
• Molecular function: serine-type endopeptidase activity;calcium ion binding;protein binding;misfolded protein binding