GeneBe

F11

protein-coding

coagulation factor XI

Gene summary

This gene encodes coagulation factor XI of the blood coagulation cascade. This protein is present in plasma as a zymogen, which is a unique plasma coagulation enzyme because it exists as a homodimer consisting of two identical polypeptide chains linked by disulfide bonds. During activation of the plasma factor XI, an internal peptide bond is cleaved by factor XIIa (or XII) in each of the two chains, resulting in activated factor XIa, a serine protease composed of two heavy and two light chains held together by disulfide bonds. This activated plasma factor XI triggers the middle phase of the intrisic pathway of blood coagulation by activating factor IX. Defects in this factor lead to Rosenthal syndrome, a blood coagulation abnormality. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000128.4

Inheritance

AD, SD, AR

ClinVar variants

P:334U:208B:165

Top phenotype

Factor XI deficiency

gnomAD constraint

pLI —, LoF o/e 1.1

Max pathogenic AF

—

Genomic locus

chr4:186,266,189-186,289,681

External References & Databases

Ensembl (ENSG00000088926)NCBI Gene (2160)OMIM (264900)HGNC:3529GenCCUniProt (P03951)AlphaFoldClinVar (F11)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~23.5 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital factor XI deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012897

Submitter: Labcorp Genetics (formerly Invitae)

congenital factor XI deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0012897

Submitter: PanelApp Australia

factor XI deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0020587

Submitter: Natera

congenital factor XI deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012897

Submitter: Orphanet

congenital factor XI deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012897

Submitter: Labcorp Genetics (formerly Invitae)

congenital factor XI deficiencyDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0012897

Submitter: ClinGen

The relationship between F11 and congenital factor XI deficiency inherited in the autosomal recessive and dominant patterns has been evaluated using the ClinGen Clinical Validity Framework as of November, 2018. This association was made using case-level and experimental data. More than a 100 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift, missense and splicing variants. Congenital Factor XI deficiency is characterized by a bleeding diathesis, diagnosed by a prolonged aPTT but normal PT and reduced factor XI activity and antigen levels. Mutations in F11 were first associated with this disease in humans as early as 1989 by Asakai et al. (PMID: 2813350). Summary of Case Level Data (12 points): The association is seen in at least 10 probands in 5 publications (PMID: 15026311, 15953011, 15180874, 21649796, 2813350, 22159456). 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 has been reported to be biallelic loss of function as well as a dominant negative effect (PMID: 15026311, 2813350). Summary of Experimental Data (4.5 points): FXI activates FIX in the blood coagulation pathway (PMID: 3286010). Mouse and cattle models are reported that recapitulate FXI deficiency (PMID: 15566468, 9518045). In Holstein cows, FXI deficiency is naturally occurring and leads to bleeding symptoms. The deficiency is also reported in dogs (PMID: 5166932). In summary, the F11-Congenital FXI 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 October 23, 2019 (SOP Version 6).

Clinical Genomic Database (CGD)

Factor XI deficiencyAD/AR

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: Individuals may be at risk of bleeding (eg, following surgery or with injury, and during delivery), and prophylaxis and preventive measures (eg, including avoidance of aspirin) and prompt treatment (eg, with fresh frozen plasma) may be beneficial, including considerations prior to/during pregnancy; Antifibrinolytic therapy may be beneficial in females with menorrhagia

Comments: Heterozygotes may have manifestations that warrant interventions

Refs: 3871646; 2439152; 3553944; 2813350; 8800510; 18434707; 18160615; 19598070; 19367158; 19049995; 21577094; 21699628; 22624777; 22726099Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to F11 variants in ClinVar

14 Conditions Cataloged
not providedTotal: 463
Hereditary factor XI deficiency diseaseTotal: 368
Plasma factor XI deficiencyTotal: 193
Inborn genetic diseasesTotal: 66
not specifiedTotal: 62
F11-related disorderTotal: 52
F11-related disordersTotal: 12
Factor XI deficiencyTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000128.4. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
11
clinvar
151
clinvar
1
clinvar
 164
missense
6
clinvar
77
clinvar
194
clinvar
12
clinvar
 289
nonsense
38
clinvar
31
clinvar
1
clinvar
 70
start loss
2
clinvar
 2
frameshift
101
clinvar
39
clinvar
2
clinvar
 142
splice donor/acceptor (+/-2bp)
7
clinvar
32
clinvar
1
clinvar
 40
Total1521822081641707

Highest pathogenic variant AF is 0.0006040638

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 86 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000128.4RefSeqNP_000119.114MANE Select
ENST00000403665.7EnsemblENSP00000384957.214MANE Select
NM_001354804.2RefSeqNP_001341733.14Standard
NM_001440590.1RefSeqNP_001427519.114Standard

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

  • blood coagulation
  • blood coagulation, intrinsic pathway
  • plasminogen activation
  • positive regulation of fibrinolysis

Molecular Function

  • serine-type endopeptidase activity
  • protein binding
  • heparin binding
  • serine-type aminopeptidase activity

Cellular Component

  • extracellular region
  • extracellular space
  • plasma membrane
  • membrane
  • extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000403665
Coding exons
14
Length
23737
Individuals with no LoFs
125376
Homozygous LoFs
3
Heterozygous LoFs
369
Defined
125748
p
0.00148
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.01993423430.9970.00001954099
Missense (PolyPhen)136137.480.989221684
Synonymous-0.4871371301.050.000008611166
Loss of Function-0.5303733.71.100.00000172414

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000430.00043rare
Latino/Admixed American0.000380.00038rare
Ashkenazi Jewish0.0170.017notable
East Asian0.00330.0033notable
Finnish0.0000920.000092rare
European (Non-Finnish)0.000710.00071rare
South Asian0.000880.00088rare
Other0.00210.0021notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Factor XI triggers the middle phase of the intrinsic pathway of blood coagulation by activating factor IX.;
Disease
DISEASE: Factor XI deficiency (FA11D) [MIM:612416]: A hemorrhagic disease characterized by reduced levels and activity of factor XI resulting in moderate bleeding symptoms, usually occurring after trauma or surgery. Patients usually do not present spontaneous bleeding but women can present with menorrhagia. Hemorrhages are usually moderate. {ECO:0000269|PubMed:10027710, ECO:0000269|PubMed:10606881, ECO:0000269|PubMed:11895778, ECO:0000269|PubMed:15026311, ECO:0000269|PubMed:15180874, ECO:0000269|PubMed:1547342, ECO:0000269|PubMed:15953011, ECO:0000269|PubMed:16607084, ECO:0000269|PubMed:18005151, ECO:0000269|PubMed:21457405, ECO:0000269|PubMed:21668437, ECO:0000269|PubMed:21999818, ECO:0000269|PubMed:22016685, ECO:0000269|PubMed:22159456, ECO:0000269|PubMed:22322133, ECO:0000269|PubMed:25158988, ECO:0000269|PubMed:2813350, ECO:0000269|PubMed:7669672, ECO:0000269|PubMed:7888672, ECO:0000269|PubMed:9401068, ECO:0000269|PubMed:9787168}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.483

Intolerance Scores

LoFtool
0.207
RVIS EVS
-0.93
RVIS percentile EVS
9.68

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.780

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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