F10

protein-coding

coagulation factor X, the group of Gla domain containing

Gene summary

This gene encodes the vitamin K-dependent coagulation factor X of the blood coagulation cascade. This factor undergoes multiple processing steps before its preproprotein is converted to a mature two-chain form by the excision of the tripeptide RKR. Two chains of the factor are held together by 1 or more disulfide bonds; the light chain contains 2 EGF-like domains, while the heavy chain contains the catalytic domain which is structurally homologous to those of the other hemostatic serine proteases. The mature factor is activated by the cleavage of the activation peptide by factor IXa (in the intrisic pathway), or by factor VIIa (in the extrinsic pathway). The activated factor then converts prothrombin to thrombin in the presence of factor Va, Ca+2, and phospholipid during blood clotting. Mutations of this gene result in factor X deficiency, a hemorrhagic condition of variable severity. 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_000504.4

Inheritance

ClinVar variants

P:54U:86B:30

Top phenotype

Factor X deficiency

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr13:113,122,799-113,149,529

External References & Databases

Ensembl (ENSG00000126218)

Transcript & Mutation Effects

hg38 • Region Span ~26.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital factor X deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009212

Submitter: Orphanet

congenital factor X deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009212

Submitter: ClinGen

The relationship between F10 and congenital factor X deficiency inherited in the autosomal recessive pattern has been evaluated using the ClinGen Clinical Validity Framework as of November, 2019. This association was made using case-level and experimental data. More than a 100 variants in this gene are reported in humans, ranging from deletions, duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor X deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT and PT and reduced Factor X activity levels. Mutations in F10 were first associated with this disease in humans as early as 1989 by Reddy et al. (PMID: 2790181). Summary of Case Level Data (12 points): The association is seen in at least 14 probands in 7 publications (PMID: 30036279, 1985698, 10746568, 30507709, 2790181, 1939653, 22931370). 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 have been reported to be biallelic loss of function, although a number of individuals with heterozygous variants showing mild to moderate FX deficiency are reported in the literature (PMID: 10746568). Some of these occurrences are noted in the genetic evidence, but not scored. Summary of Experimental Data (4.5 points): FX activates prothrombin to thrombin in the blood coagulation pathway (PMID: 3286010). Mouse models that have the F10 gene knocked out show embryonic and perinatal lethality (PMID: 27626380, 10739370, 18036190); however, the mouse model with a missense variant, FX Friuli recapitulates FX deficiency in humans. The evidence from the mouse models parallel that seen in humans, where a complete loss of FX activity has not been reported in any patients. In summary, the F10-Congenital FX 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 Nov 27, 2019. (SOP Version 7)

congenital factor X deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009212

Submitter: Ambry Genetics

congenital factor X deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009212

Submitter: PanelApp Australia

congenital factor X deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009212

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Factor X deficiencyAR

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: Individuals can suffer from bleeding diatheses of varying severity, and preventive measures related to bleeding episodes can be beneficial, including in special circumstances such as pregnancy; Precautions should be taken related to certain agents that may provoke/worsen bleeding risk

Refs: 5450692; 4989292; 4995085; 3732313; 8192155; 3408671; 2567188; 2790181; 1985698; 1997381; 9695984; 10746568; 12028042; 22151249; 22460599; 22506295

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to F10 variants in ClinVar

10 Conditions Cataloged

Hereditary factor X deficiency diseaseTotal: 70

not providedTotal: 47

Inborn genetic diseasesTotal: 33

Factor X deficiencyTotal: 27

F10-related disorderTotal: 27

not specifiedTotal: 25

Abnormal bleedingTotal: 5

F10-related disordersTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000504.4. 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			7 clinvar	20 clinvar	1 clinvar	28
missense	12 clinvar	24 clinvar	78 clinvar	7 clinvar	2 clinvar	123
nonsense	2 clinvar	1 clinvar				3
start loss						0
frameshift	3 clinvar	7 clinvar				10
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	1 clinvar			6
Total	18	36	86	27	3	170

Highest pathogenic variant AF is 0.000024176272

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000504.4	RefSeq	NP_000495.1	8	MANE Select
ENST00000375559.8	Ensembl	ENSP00000364709.3	8	MANE Select
NM_001312674.2	RefSeq	NP_001299603.1	7	Standard
NM_001312675.2	RefSeq	NP_001299604.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
f10	Danio rerio	Structure: muscle Quality: hemorrhagic abnormal

Gene / Model

Organism

Observed Phenotype

f10

Danio rerio

Structure: muscle

Quality: hemorrhagic

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

proteolysis
endoplasmic reticulum to Golgi vesicle-mediated transport
blood coagulation
blood coagulation, extrinsic pathway
positive regulation of cell migration

Molecular Function

serine-type endopeptidase activity
calcium ion binding
protein binding
phospholipid binding

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: ENST00000375559
Coding exons: 8
Length: 26716
Individuals with no LoFs: 125715
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125748
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	245	304	0.807	0.0000211	3218
Missense (PolyPhen)		86	133.73	0.64307		1399
Synonymous	0.461	126	133	0.949	0.0000109	912
Loss of Function	1.67	12	20.0	0.599	9.42e-7	235

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00024	0.00023	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00020	0.00020	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Factor Xa is a vitamin K-dependent glycoprotein that converts prothrombin to thrombin in the presence of factor Va, calcium and phospholipid during blood clotting.;
Disease: DISEASE: Factor X deficiency (FA10D) [MIM:227600]: A hemorrhagic disease with variable presentation. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. Some patients do not have clinical bleeding diathesis. {ECO:0000269|PubMed:10468877, ECO:0000269|PubMed:10739379, ECO:0000269|PubMed:10746568, ECO:0000269|PubMed:11248282, ECO:0000269|PubMed:11728527, ECO:0000269|PubMed:12574802, ECO:0000269|PubMed:12945883, ECO:0000269|PubMed:15075089, ECO:0000269|PubMed:15650540, ECO:0000269|PubMed:17393015, ECO:0000269|PubMed:19135706, ECO:0000269|PubMed:1973167, ECO:0000269|PubMed:1985698, ECO:0000269|PubMed:25313940, ECO:0000269|PubMed:26222694, ECO:0000269|PubMed:2790181, ECO:0000269|PubMed:7669671, ECO:0000269|PubMed:7860069, ECO:0000269|PubMed:8529633, ECO:0000269|PubMed:8845463, ECO:0000269|PubMed:8910490}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.456

Intolerance Scores

LoFtool: 0.107
RVIS EVS: -0.55
RVIS percentile EVS: 19.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.913

Gene Damage Prediction

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