• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
F9 (HGNC:3551) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
coagulation factor IX
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
FIX
%HI
40.27(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.17(Read more about gnomAD LOEUF score)
Cytoband
Xq27.1
Genomic Coordinates
GRCh37/hg19: chrX:138612898-138645618 NCBI Ensembl UCSC
GRCh38/hg38: chrX:139530739-139563459 NCBI Ensembl UCSC
MANE Select Transcript
NM_000133.4 ENST00000218099.7 (Read more about MANE Select)
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}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-25959
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
01/12/2021

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 20301668
    Hemophilia B is an X‐chromosome‐linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX (F9) activity levels may also experience some bleeding. Hemophilia B has a prevalence of approximately 1 in 30,000 males. Loss-of-function variants in the F9 gene are a known cause of this disorder. Numerous deletions and loss-of-function point mutations are reported in public/commercial databases (see MIM: #300746 and GeneReviews).
  • PUBMED: 29296726
    Johnsen et al. (2017) used an NGS-based approach to genotype hemophilia patients in a large study comprising of approximately 15% of hemophilia cases in the United States and detected a causative variant in the F9 gene in 595/599 individuals with hemophilia B, including 217 previously unreported unique variants. Missense variants accounted for most of the variants detected in males with mild or moderate hemophilia B (87%). Nonsense, frameshift, and larger (>50 bp) SVs including inversions made up to 45% of variants detected in males with severe hemophilia B, consistent with the predicted negative impact of these types of variants on gene function.
HI Evidence Comments:
Deletions and loss of function mutations in F9 result in hemophilia B in males. Deletions or duplications of exons resulting in loss of function account for 3% of all mutations. Heterozygous females are typically unaffected carriers but may have abnormal bleeding, depending on their F9 clotting activity levels. See Gene Reviews. Loss-of-function variants in F9 are a known cause of hemophilia B with deletions and loss-of-function point mutations representing the majority of cases. Pinotti (2012) demonstrated the mechanisms through which F9 nonsense mutations impair gene expression include ribosome readthrough, which consists of misrecognition of the premature stop codon by an aminoacyl-tRNA instead of the termination factors. Hemophilia patients with nonsense mutations have a lower risk of developing inhibitors than patients with larger gene deletions. F9 coagulent activity levels were determined by aPTT-based assays and F9 proteins levels by ELISA. F9 mRNA levels were detected by reverse transcription followed by RT-PCR and expression studies in HEK293 cells. Ribosome readthrough may account for minimal full-length protein biosynthesis in a small number of HB cases that are caused by the R162*, R294*, R298* mutations, which showed appreciable levels of secreted F9 protein in vitro and in vivo (PMID: 22618954). Recurring mutations commonly occur as founder mutations in some populations. Lasalle (2017) identified recurrent variant c.835G>A (p.Ala279Thr) in 34 HB patients from two different regions of France representing the largest cohort of hemophilia patients with an identical variant. Haplotype reconstruction of extragenic and intragenic polymorphic markers was performed to demonstrate a founder effect for this variant. Recurrence of the other approximately 1,000 different F9 variants was shown to remain limited (PMID: 29296726).
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
NOTE:

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)