F7

protein-coding

coagulation factor VII, the group of Gla domain containing

Gene summary

This gene encodes coagulation factor VII which is a vitamin K-dependent factor essential for hemostasis. This factor circulates in the blood in a zymogen form, and is converted to an active form by either factor IXa, factor Xa, factor XIIa, or thrombin by minor proteolysis. Upon activation of the factor VII, a heavy chain containing a catalytic domain and a light chain containing 2 EGF-like domains are generated, and two chains are held together by a disulfide bond. In the presence of factor III and calcium ions, the activated factor then further activates the coagulation cascade by converting factor IX to factor IXa and/or factor X to factor Xa. Defects in this gene can cause coagulopathy. Alternative splicing results in multiple transcript variants encoding different isoforms that may undergo similar proteolytic processing to generate mature polypeptides. [provided by RefSeq, Aug 2015]

MANE transcript

NM_019616.4

Inheritance

ClinVar variants

P:99U:124B:23

Top phenotype

Factor VII deficiency

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr13:113,105,788-113,120,685

External References & Databases

Ensembl (ENSG00000057593)

Transcript & Mutation Effects

hg38 • Region Span ~14.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital factor VII deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009211

Submitter: Ambry Genetics

factor VII deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0002244

Submitter: ClinGen

F7 was reported in relation to autosomal recessive Factor VII deficiency as early as 1996 (Arbini et al., PMID: 8652821). More than 100 pathogenic variants in this gene are reported in humans, ranging from deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Factor VII deficiency is characterized by a bleeding diathesis, with an increased prothrombin time, but normal activated partial thromboplastin time, reduced Factor VII activity and antigen levels. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 9 probands in 6 publications (PMIDs: 8652821, 11091194, 22628013, 10959697, 23141848, 11529858). More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is homozygous loss of function. Summary of Experimental Data (4.5 points): FVII is involved in the blood coagulation pathway and functions to activate FX in complex with Tissue Factor (PMID: 3286010). Mouse models recapitulate the human bleeding phenotype, but bleeding is more severe in mice (PMID: 9384381). AAV-mediated expression of FVII is shown to rescue bleeding in dog models (PMID: 26702064). In summary, the F7-Factor VII 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.

congenital factor VII deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009211

Submitter: PanelApp Australia

congenital factor VII deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009211

Submitter: Labcorp Genetics (formerly Invitae)

congenital factor VII deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009211

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.

congenital factor VII deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009211

Submitter: Orphanet

Clinical Genomic Database (CGD)

Factor VII deficiencyAR

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: Individuals can suffer from bleeding diatheses of varying severity, and preventive measures and prompt treatment (including with factor replacement therapy) related to bleeding episodes can be beneficial; Precautions should be taken related to certain agents that may provoke/worsen bleeding risk

Refs: 7919338; 7981691; 8652821; 8883260; 9680360; 11091194; 10984565; 11129332; 10862079; 11225604; 11139238; 11260055; 12181036; 11529858; 22188821; 22327818; 22356641; 22628013; 22684392; 22845882; 22873696; 22974900

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to F7 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 99

Congenital factor VII deficiencyTotal: 97

Factor VII deficiencyTotal: 74

Inborn genetic diseasesTotal: 65

F7-related disorderTotal: 36

not specifiedTotal: 35

Myocardial infarction, susceptibility toTotal: 28

Abnormal bleedingTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_019616.4. 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		1 clinvar	5 clinvar	13 clinvar	2 clinvar	21
missense	13 clinvar	53 clinvar	118 clinvar	8 clinvar		192
nonsense	7 clinvar	7 clinvar				14
start loss		1 clinvar				1
frameshift	3 clinvar	6 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	4 clinvar	4 clinvar				8
Total	27	72	124	21	2	246

Highest pathogenic variant AF is 0.000400562

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_019616.4	RefSeq	NP_062562.1	8	MANE Select
ENST00000346342.8	Ensembl	ENSP00000329546.4	8	MANE Select
NM_000131.5	RefSeq	NP_000122.1	9	Standard
NM_001267554.2	RefSeq	NP_001254483.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
f7	Danio rerio	Structure: blood coagulation, fibrin clot formation Quality: delayed abnormal

Gene / Model

Organism

Observed Phenotype

Danio rerio

Structure: blood coagulation, fibrin clot formation

Quality: delayed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
Warfarin Pathway, Pharmacodynamics
Aminocaproic Acid Action Pathway
Tranexamic Acid Action Pathway
Urokinase Action Pathway

Biological Process

response to hypoxia
positive regulation of leukocyte chemotaxis
endoplasmic reticulum to Golgi vesicle-mediated transport
blood coagulation
blood coagulation, extrinsic pathway

Molecular Function

serine-type endopeptidase activity
signaling receptor binding
calcium ion binding
protein binding
serine-type peptidase activity

Cellular Component

extracellular region
extracellular space
endoplasmic reticulum lumen
Golgi lumen
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000375581
Coding exons: 9
Length: 14891
Individuals with no LoFs: 125537
Homozygous LoFs: 0
Heterozygous LoFs: 208
Defined: 125745
p: 0.000827

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.320	289	305	0.948	0.0000202	3002
Missense (PolyPhen)		106	123.31	0.8596		1246
Synonymous	1.22	116	134	0.866	0.00000951	942
Loss of Function	1.89	11	20.2	0.545	0.00000105	221

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.0017	0.0017	notable
Ashkenazi Jewish	0.00080	0.00079	rare
East Asian	0.00071	0.00071	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00094	0.00094	rare
South Asian	0.00029	0.00029	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Initiates the extrinsic pathway of blood coagulation. Serine protease that circulates in the blood in a zymogen form. Factor VII is converted to factor VIIa by factor Xa, factor XIIa, factor IXa, or thrombin by minor proteolysis. In the presence of tissue factor and calcium ions, factor VIIa then converts factor X to factor Xa by limited proteolysis. Factor VIIa will also convert factor IX to factor IXa in the presence of tissue factor and calcium.;
Disease: DISEASE: Factor VII deficiency (FA7D) [MIM:227500]: A hemorrhagic disease with variable presentation. The clinical picture can be very severe, with the early occurrence of intracerebral hemorrhages or repeated hemarthroses, or, in contrast, moderate with cutaneous-mucosal hemorrhages (epistaxis, menorrhagia) or hemorrhages provoked by a surgical intervention. Finally, numerous subjects are completely asymptomatic despite very low factor VII levels. {ECO:0000269|PubMed:10862079, ECO:0000269|PubMed:11091194, ECO:0000269|PubMed:11129332, ECO:0000269|PubMed:12472587, ECO:0000269|PubMed:14717781, ECO:0000269|PubMed:1634227, ECO:0000269|PubMed:18976247, ECO:0000269|PubMed:19432927, ECO:0000269|PubMed:19751712, ECO:0000269|PubMed:2070047, ECO:0000269|PubMed:21206266, ECO:0000269|PubMed:21372693, ECO:0000269|PubMed:26761581, ECO:0000269|PubMed:7974346, ECO:0000269|PubMed:7981691, ECO:0000269|PubMed:8043443, ECO:0000269|PubMed:8204879, ECO:0000269|PubMed:8242057, ECO:0000269|PubMed:8364544, ECO:0000269|PubMed:8652821, ECO:0000269|PubMed:8844208, ECO:0000269|PubMed:8883260, ECO:0000269|PubMed:8940045, ECO:0000269|PubMed:9414278, ECO:0000269|PubMed:9452082, ECO:0000269|PubMed:9576180}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.268

Intolerance Scores

LoFtool: 0.0655
RVIS EVS: -0.02
RVIS percentile EVS: 52.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.782

Gene Damage Prediction

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