GeneBe

F8

protein-coding

coagulation factor VIII

Gene summary

This gene encodes coagulation factor VIII, which participates in the intrinsic pathway of blood coagulation; factor VIII is a cofactor for factor IXa which, in the presence of Ca+2 and phospholipids, converts factor X to the activated form Xa. This gene produces two alternatively spliced transcripts. Transcript variant 1 encodes a large glycoprotein, isoform a, which circulates in plasma and associates with von Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events. Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity. Defects in this gene results in hemophilia A, a common recessive X-linked coagulation disorder. [provided by RefSeq, Jul 2008]

Previous symbols:
  • F8C

MANE transcript

NM_000132.4

Inheritance

XL

ClinVar variants

P:703U:668B:101

Top phenotype

Hemophilia A; Thrombophilia 13, X-linked, due to factor VIII defect

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chrX:154,835,788-155,026,940

External References & Databases

Ensembl (ENSG00000185010)NCBI Gene (2157)OMIM (300841)HGNC:3546GenCCUniProt (P00451)AlphaFoldClinVar (F8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~191.2 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hemophilia ASTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010602

Submitter: Labcorp Genetics (formerly Invitae)

symptomatic form of hemophilia A in female carriersSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0015787

Submitter: Orphanet

hemophilia ADEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010602

Submitter: ClinGen

F8 was reported in relation to X-linked Hemophilia A as early as 1985 (Gitschier et al., PMID: 2987704). More than 1000 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Hemophilia A is characterized by severe bleeding diagnosed by an increased bleeding time, reduced Factor VIII activity and antigen levels. Spontaneous bleeding into joints and soft tissues is often reported. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 14 probands in 8 publications (PMIDs: 2987704, 30210749, 3035554, 10886198, 8281136, 2105106, 16805874, 28252515). Variants in this gene segregated with disease in 10 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is hemizygous loss of function in males, with the majority of variants observed resulting in undetectable FVIII activity (PMID: 2987704). Homozygous loss of function is reported in some female patients with severe bleeding diathesis, while most females are heterozygous carriers. A proportion of patients with null variants are reported to develop antibodies to recombinant FVIII. (PMIDs: 24498605, 22102273, 20081061, 19336737). Summary of Experimental Data (4.5 points): FVIII is involved in the blood coagulation pathway and functions to activate FX by forming the tenase complex with FIX (PMID: 3286010). Hemophilia A has been studied in dogs since 1950 (PMID: 15431070, 24253479, 22137432), while horse (PMID: 6838443) and mouse models (PMID: 7647782, 24705491) also have been used extensively in Hemophilia research. These animal models have been helpful in the development of recombinant FVIII for treatment of Hemophilia A. The F8 gene disruption results in loss of function and absence of detectable FVIII:C in mice with a phenotype of severe bleeding. This is shown to be rescued by RNA trans-splicing to yield a full-length, wild-type protein in FVIII-deficient mice. Gene therapy in humans for Hemophilia A using recombinant adeno-associated virus (rAAV)–mediated gene transfer is at the clinical trials stage. In summary, the F8-Hemophilia A gene-disease relationship is Definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

severe hemophilia ASUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0015719

Submitter: Orphanet

mild hemophilia ASUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0015721

Submitter: Orphanet

moderately severe hemophilia ASUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0015720

Submitter: Orphanet

hemophilia ASTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010602

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hemophilia A; Thrombophilia 13, X-linked, due to factor VIII defectXL

Manifestation: Hematologic

Intervention: Hematologic; Pharmacogenomic

Rationale: In people with Hemophilia A, plasma-derived factor VIII concentrate and/or desmopressin can be used to treat/prevent bleeding, 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; Individuals with Thrombophilia 13 may be at increased risk of blood clots, and awareness may allow medical management (eg, with heparin-related agents and warfarin) and prompt management of sequelae

Refs: 13739554; 2987704; 3012775; 3035554; 3097553; 3338800; 3131627; 2833855; 2835904; 3139545; 1688823; 2123300; 1357455; 8275087; 8281136; 8259143; 7662970; 3893256; 8644728; 8968748; 9042915; 11023529; 11396445; 11857744; 12907007; 16786531; 16551972; 18691168; 18217193; 20301578; 21056901; 22507546; 22621702; 22639879; 22866674; 23005041; 23025325; 23047359; 23067060; 29224506; 33275657Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to F8 variants in ClinVar

26 Conditions Cataloged
Hereditary factor VIII deficiency diseaseTotal: 730
not providedTotal: 397
not specifiedTotal: 197
F8-related disorderTotal: 131
Inborn genetic diseasesTotal: 122
Thrombophilia, X-linked, due to factor 8 defectTotal: 62
Hereditary factor IX deficiency diseaseTotal: 57
Factor VIII deficiencyTotal: 24

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000132.4. 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
4
clinvar
48
clinvar
47
clinvar
6
clinvar
 106
missense
159
clinvar
277
clinvar
544
clinvar
40
clinvar
8
clinvar
 1028
nonsense
77
clinvar
12
clinvar
34
clinvar
 123
start loss
1
clinvar
1
clinvar
 2
frameshift
104
clinvar
30
clinvar
 134
splice donor/acceptor (+/-2bp)
22
clinvar
16
clinvar
41
clinvar
 79
Total36433966887141472

Highest pathogenic variant AF is 0.00024064483

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000132.4RefSeqNP_000123.126MANE Select
ENST00000360256.9EnsemblENSP00000353393.426MANE Select
NM_019863.3RefSeqNP_063916.15Standard
ENST00000330287.10EnsemblENSP00000327895.65Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
f8Danio rerio

Structure: thrombocyte

Quality: distributed

abnormal

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

  • platelet degranulation
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • acute-phase response
  • blood coagulation
  • blood coagulation, intrinsic pathway

Molecular Function

  • copper ion binding
  • protein binding
  • oxidoreductase activity

Cellular Component

  • Golgi membrane
  • extracellular region
  • extracellular space
  • endoplasmic reticulum lumen
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000360256
Coding exons
26
Length
191153
Individuals with no LoFs
125740
Homozygous LoFs
1
Heterozygous LoFs
3
Defined
125744
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.476428440.7610.000060615592
Missense (PolyPhen)85273.660.310614952
Synonymous1.372743040.9000.00002194421
Loss of Function7.55270.40.02840.000005251274

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000370.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000620.000046rare
European (Non-Finnish)0.0000240.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.;
Disease
DISEASE: Hemophilia A (HEMA) [MIM:306700]: A disorder of blood coagulation characterized by a permanent tendency to hemorrhage. About 50% of patients have severe hemophilia resulting in frequent spontaneous bleeding into joints, muscles and internal organs. Less severe forms are characterized by bleeding after trauma or surgery. {ECO:0000269|PubMed:10215414, ECO:0000269|PubMed:10338101, ECO:0000269|PubMed:10404764, ECO:0000269|PubMed:10408784, ECO:0000269|PubMed:10554831, ECO:0000269|PubMed:10612839, ECO:0000269|PubMed:10691849, ECO:0000269|PubMed:10800171, ECO:0000269|PubMed:10886198, ECO:0000269|PubMed:10896236, ECO:0000269|PubMed:10910910, ECO:0000269|PubMed:10910913, ECO:0000269|PubMed:11298607, ECO:0000269|PubMed:11341489, ECO:0000269|PubMed:11410838, ECO:0000269|PubMed:11442643, ECO:0000269|PubMed:11442647, ECO:0000269|PubMed:11554935, ECO:0000269|PubMed:11748850, ECO:0000269|PubMed:11857744, ECO:0000269|PubMed:11858487, ECO:0000269|PubMed:12195713, ECO:0000269|PubMed:12199686, ECO:0000269|PubMed:12203998, ECO:0000269|PubMed:12325022, ECO:0000269|PubMed:12351418, ECO:0000269|PubMed:12406074, ECO:0000269|PubMed:12614369, ECO:0000269|PubMed:12871415, ECO:0000269|PubMed:12930394, ECO:0000269|PubMed:1301194, ECO:0000269|PubMed:1301932, ECO:0000269|PubMed:1301960, ECO:0000269|PubMed:1349567, ECO:0000269|PubMed:1356412, ECO:0000269|PubMed:15682412, ECO:0000269|PubMed:15810915, ECO:0000269|PubMed:1639429, ECO:0000269|PubMed:16805874, ECO:0000269|PubMed:18184865, ECO:0000269|PubMed:1851341, ECO:0000269|PubMed:1908096, ECO:0000269|PubMed:1908817, ECO:0000269|PubMed:1973901, ECO:0000269|PubMed:2104766, ECO:0000269|PubMed:2105106, ECO:0000269|PubMed:2105906, ECO:0000269|PubMed:2106480, ECO:0000269|PubMed:2107542, ECO:0000269|PubMed:21371196, ECO:0000269|PubMed:2495245, ECO:0000269|PubMed:2498882, ECO:0000269|PubMed:2499363, ECO:0000269|PubMed:2506948, ECO:0000269|PubMed:2510835, ECO:0000269|PubMed:25550078, ECO:0000269|PubMed:26278069, ECO:0000269|PubMed:2833855, ECO:0000269|PubMed:2835904, ECO:0000269|PubMed:3012775, ECO:0000269|PubMed:3122181, ECO:0000269|PubMed:7579394, ECO:0000269|PubMed:7759074, ECO:0000269|PubMed:7794769, ECO:0000269|PubMed:8322269, ECO:0000269|PubMed:8449505, ECO:0000269|PubMed:8639447, ECO:0000269|PubMed:8644728, ECO:0000269|PubMed:8759905, ECO:0000269|PubMed:9029040, ECO:0000269|PubMed:9326186, ECO:0000269|PubMed:9341862, ECO:0000269|PubMed:9450898, ECO:0000269|PubMed:9452104, ECO:0000269|PubMed:9569180, ECO:0000269|PubMed:9569189, ECO:0000269|PubMed:9603440, ECO:0000269|PubMed:9792405, ECO:0000269|PubMed:9829908, ECO:0000269|PubMed:9886318}. Note=The disease is caused by mutations affecting the gene represented in this entry. Of particular interest for the understanding of the function of F8 is the category of CRM (cross-reacting material) positive patients (approximately 5%) that have considerable amount of F8 in their plasma (at least 30% of normal), but the protein is non- functional; i.e. the F8 activity is much less than the plasma protein level. CRM-reduced is another category of patients in which the F8C antigen and activity are reduced to approximately the same level. Most mutations are CRM negative, and probably affect the folding and stability of the protein.;

Recessive Scores

pRec
0.829

Intolerance Scores

LoFtool
0.00158
RVIS EVS
-0.75
RVIS percentile EVS
13.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.619

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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