F9

coagulation factor IX, the group of Gla domain containing

Basic information

Region (hg38): X:139530739-139563459

Links

ENSG00000101981 ∙ NCBI:2158 ∙ OMIM:300746 ∙ HGNC:3551 ∙ Uniprot:P00740 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• severe hemophilia B (Supportive), mode of inheritance: XL
• moderately severe hemophilia B (Supportive), mode of inheritance: XL
• mild hemophilia B (Supportive), mode of inheritance: XL
• symptomatic form of hemophilia B in female carriers (Supportive), mode of inheritance: XL
• hemophilia B (Definitive), mode of inheritance: XL
• thrombophilia, X-linked, due to factor 9 defect (Limited), mode of inheritance: XL
• hemophilia B (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hemophilia B; Thrombophilia, X-linked, due to factor IX defect; Warfarin sensitivity, X-linked	XL	Hematologic; Pharmacogenomic	In Hemophilia B, recombinant or plasma-derived factor IX concentrate can be effective for prevention/treatment of bleeding episodes, and gene therapy has been described as beneficial; Other considerations may be beneficial in specific circumstances, such as in postpartum females; Certain circumstances should be avoided or need to be specifically managed, such as circumcision, high-risk activities, and medications such as aspirin; In X-linked thrombophilia, preventive measures related to thrombophilia, as well as early recognition and treatment of manifestations such as deep venous thromboses, may reduce morbidity	Hematologic	14920537; 12997790; 4163943; 4972271; 5781711; 5450691; 734633; 7062952; 6142993; 3001143; 2907054; 3219291; 2841226; 2570235; 1768766; 1873221; 1601420; 8392713; 8352232; 8096443; 8304338; 8594556; 8833911; 9016521; 9233593; 10845896; 11122385; 11328285; 18349091; 18624978; 19251637; 19815722; 19846852; 20301668; 21056901; 29211678; 36812434

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the F9 gene.

• Hereditary factor IX deficiency disease (36 variants)
• not specified (33 variants)
• Thrombophilia, X-linked, due to factor 9 defect;Hereditary factor IX deficiency disease (33 variants)
• Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect (27 variants)
• not provided (15 variants)
• Hereditary factor VIII deficiency disease (9 variants)
• F9-related disorder (4 variants)
• Thrombophilia, X-linked, due to factor 9 defect (3 variants)
• Abnormality of coagulation (2 variants)
• Hemophilia b(m) (1 variants)
• Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect;Warfarin sensitivity, X-linked (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the F9 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		1	1	115	16	133
missense	60	62	49	13	8	192
nonsense	24	1				25
start loss						0
frameshift	8					8
inframe indel		1				1
splice donor/acceptor (+/-2bp)	8	2				10
splice region	3	4	3	11	2	23
non coding		2	11	42	7	62
Total	100	69	61	170	31

Highest pathogenic variant AF is 0.0000359

Variants in F9

This is a list of pathogenic ClinVar variants found in the F9 region.

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

Position	Type	Phenotype	Significance	ClinVar
X-139530743-T-C		Hemophilia B leyden	Pathogenic (Feb 01, 1991)
X-139530746-C-G		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Uncertain significance (Jul 31, 2021)
X-139530746-CA-C		Hemophilia B leyden	Pathogenic (May 31, 1990)
X-139530748-A-G		Hemophilia B leyden • Thrombophilia, X-linked, due to factor 9 defect;Hereditary factor IX deficiency disease	Likely pathogenic (Jan 30, 2023)
X-139530771-C-A		Thrombophilia, X-linked, due to factor 9 defect;Hereditary factor IX deficiency disease	Likely benign (Jun 09, 2023)
X-139530771-C-T		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • Hereditary factor IX deficiency disease	Benign (Oct 26, 2023)
X-139530772-G-A		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • Hereditary factor IX deficiency disease • not specified • Hereditary factor IX deficiency disease;Warfarin sensitivity, X-linked;Thrombophilia, X-linked, due to factor 9 defect • F9-related disorder	Benign (Feb 09, 2024)
X-139530773-C-G		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Likely benign (Jan 19, 2023)
X-139530773-C-T		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • Hereditary factor IX deficiency disease	Likely benign (Oct 22, 2023)
X-139530779-C-T		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Likely benign (Dec 18, 2021)
X-139530783-A-T		Hereditary factor IX deficiency disease • Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • FACTOR IX POLYMORPHISM • Warfarin sensitivity, X-linked;Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • F9-related disorder	Benign (Feb 09, 2024)
X-139530786-A-G		F9-related disorder	Uncertain significance (Apr 30, 2024)
X-139530790-C-G		F9-related disorder	Uncertain significance (Jun 20, 2024)
X-139530791-A-C		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Likely benign (Nov 17, 2023)
X-139530795-T-A		Hereditary factor IX deficiency disease	Pathogenic (Jan 01, 1993)
X-139530800-A-G		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Likely benign (Apr 13, 2022)
X-139530800-AG-A		not specified	Pathogenic (May 06, 2019)
X-139530808-T-A		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Uncertain significance (Jan 01, 2021)
X-139530812-C-A		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • Hereditary factor IX deficiency disease	Benign (Jan 04, 2024)
X-139530815-C-T		Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect • Hereditary factor IX deficiency disease	Benign (Feb 09, 2024)
X-139530816-T-C		Hereditary factor IX deficiency disease	Pathogenic (Oct 09, 2017)
X-139530818-C-T		Hereditary factor IX deficiency disease • Hereditary factor IX deficiency disease;Thrombophilia, X-linked, due to factor 9 defect	Likely benign (Apr 28, 2022)
X-139530824-A-G		Thrombophilia, X-linked, due to factor 9 defect;Hereditary factor IX deficiency disease • Hereditary factor IX deficiency disease	Benign (Feb 09, 2024)
X-139530825-G-A			Uncertain significance (Apr 23, 2024)
X-139530832-T-C		Hereditary factor IX deficiency disease	Pathogenic (Jun 23, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
F9	protein_coding	protein_coding	ENST00000218099	8	32701

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.998	0.00224	125151	0	1	125152	0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.18	93	174	0.535	0.0000128	3042
Missense in Polyphen		18	73.466	0.24501		1278
Synonymous	-1.25	73	60.7	1.20	0.00000451	843
Loss of Function	3.92	0	17.9	0.00	0.00000153	284

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000123	0.00000885
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa. {ECO:0000269|PubMed:1730085, ECO:0000269|PubMed:19846852, ECO:0000269|PubMed:20121197, ECO:0000269|PubMed:20121198, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:8295821}.
• Disease: DISEASE: Hemophilia B (HEMB) [MIM:306900]: An X-linked blood coagulation disorder characterized by a permanent tendency to hemorrhage, due to factor IX deficiency. It is phenotypically similar to hemophilia A, but patients present with fewer symptoms. Many patients are asymptomatic until the hemostatic system is stressed by surgery or trauma. {ECO:0000269|PubMed:10094553, ECO:0000269|PubMed:10698280, ECO:0000269|PubMed:11122099, ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:12604421, ECO:0000269|PubMed:1346975, ECO:0000269|PubMed:1615485, ECO:0000269|PubMed:1902289, ECO:0000269|PubMed:1958666, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:2339358, ECO:0000269|PubMed:2372509, ECO:0000269|PubMed:2472424, ECO:0000269|PubMed:25251685, ECO:0000269|PubMed:25470321, ECO:0000269|PubMed:2592373, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2714791, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:2753873, ECO:0000269|PubMed:2773937, ECO:0000269|PubMed:2775660, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3243764, ECO:0000269|PubMed:3401602, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:7981722, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8199596, ECO:0000269|PubMed:8257988, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:8680410, ECO:0000269|PubMed:9169594, ECO:0000269|PubMed:9222764, ECO:0000269|PubMed:9452115, ECO:0000269|PubMed:9590153, ECO:0000269|PubMed:9600455}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide (PubMed:12588353, PubMed:2738071, PubMed:3009023, PubMed:8295821, PubMed:9169594, PubMed:9600455, PubMed:25251685). Mutation in position 93 (Alabama) probably fails to bind to cell membranes (PubMed:3790720). Mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya or Hilo) prevent cleavage of the activation peptide (PubMed:6603618, PubMed:8076946, PubMed:12588353, PubMed:2162822, PubMed:25251685, PubMed:2713493). {ECO:0000269|PubMed:12588353, ECO:0000269|PubMed:2162822, ECO:0000269|PubMed:25251685, ECO:0000269|PubMed:2713493, ECO:0000269|PubMed:2738071, ECO:0000269|PubMed:3009023, ECO:0000269|PubMed:3790720, ECO:0000269|PubMed:6603618, ECO:0000269|PubMed:8076946, ECO:0000269|PubMed:8295821, ECO:0000269|PubMed:9169594, ECO:0000269|PubMed:9600455}.; DISEASE: Thrombophilia, X-linked, due to factor IX defect (THPH8) [MIM:300807]: A hemostatic disorder characterized by a tendency to thrombosis. {ECO:0000269|PubMed:19846852}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Complement and coagulation cascades - Homo sapiens (human);Warfarin Pathway, Pharmacodynamics;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;platelet amyloid precursor protein pathway;intrinsic prothrombin activation pathway;Post-translational protein modification;Metabolism of proteins;Gamma-carboxylation of protein precursors;Removal of aminoterminal propeptides from gamma-carboxylated proteins;Gamma-carboxylation, transport, and amino-terminal cleavage of proteins;Gamma carboxylation, hypusine formation and arylsulfatase activation;Extrinsic Pathway of Fibrin Clot Formation;Intrinsic Pathway of Fibrin Clot Formation;Hemostasis;Formation of Fibrin Clot (Clotting Cascade) (Consensus)

Recessive Scores

• pRec: 0.572

Intolerance Scores

• rvis_EVS: -0.03
• rvis_percentile_EVS: 51.66

Haploinsufficiency Scores

• pHI: 0.347
• hipred: Y
• hipred_score: 0.749
• ghis: 0.423

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.697

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: F9
• Phenotype: homeostasis/metabolism phenotype; immune system phenotype; embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype

Gene ontology

• Biological process: proteolysis;endoplasmic reticulum to Golgi vesicle-mediated transport;blood coagulation;blood coagulation, intrinsic pathway;zymogen activation
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;Golgi lumen;plasma membrane;extracellular exosome
• Molecular function: endopeptidase activity;serine-type endopeptidase activity;calcium ion binding;protein binding