Incidental Mutation 'G5030:F3'

• ID: 507
• Institutional Source: Beutler Lab
• Gene Symbol: F3
• Ensembl Gene: ENSMUSG00000028128
• Gene Name: coagulation factor III
• Synonyms: Cf-3, tissue factor, TF, Cf3, CD142
• Essential gene?: Probably non essential (E-score: 0.067)
• Stock #: G5030 (G3) of strain 560
• Status: Validated
• Chromosome: 3
• Chromosomal Location: 121517186-121528697 bp(+) (GRCm39)
• Type of Mutation: missense
• DNA Base Change (assembly): T to A at 121518648 bp (GRCm39)
• Zygosity: Homozygous
• Amino Acid Change: Asparagine to Lysine at position 37 (N37K)
• Ref Sequence: ENSEMBL: ENSMUSP00000029771
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000029771]
• AlphaFold: no structure available at present
• Predicted Effect: probably damaging; Transcript: ENSMUST00000029771; AA Change: N37K; PolyPhen 2 Score 1.000 (Sensitivity: 0.00; Specificity: 1.00)
• SMART Domains: Protein: ENSMUSP00000029771; Gene: ENSMUSG00000028128; AA Change: N37K

Domain	Start	End	E-Value	Type
Pfam:Tissue_fac	12	110	1.1e-26	PFAM
Pfam:Interfer-bind	138	245	5.1e-26	PFAM
transmembrane domain	253	275	N/A	INTRINSIC

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000196746
• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000197391
• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000197731
• Predicted Effect: probably benign; Transcript: ENSMUST00000199997
• Meta Mutation Damage Score: 0.5491
• Coding Region Coverage:
  • 1x: 81.1%
  • 3x: 60.2%
• Het Detection Efficiency: 35.6%
• Validation Efficiency: 87% (206/237)
• MGI Phenotype: FUNCTION: This gene encodes a membrane-bound glycoprotein that forms the primary physiological initiator of the blood coagulation process following vascular damage. The encoded protein binds to coagulation factor VIIa and the ensuing complex catalyzes the proteolytic activation of coagulation factors IX and X. Mice lacking encoded protein die in utero resulting from massive hemorrhaging in both extraembryonic and embryonic vessels. A severe deficiency of the encoded protein in mice results in impaired uterine homeostasis, shorter life spans due to spontaneous fatal hemorrhages and cardiac fibrosis. [provided by RefSeq, Aug 2015] ; PHENOTYPE: Homozygotes for targeted null mutations exhibit impaired blood vessel development, retarded growth, and, in most cases, midgestational lethality. On a mixed background, some mutants survive to birth and appear to be normal. [provided by MGI curators]
• Allele List at MGI:

  All alleles(7) : Targeted, knock-out(5) Targeted, other(2)

• Posted On: 2010-10-26

Nature of Mutation

DNA sequencing using the SOLiD technique identified a T to A transversion at position 289 of the F3 transcript in exon 2 of 6 total exons. Two transcripts of the F3 gene are displayed on Ensembl. The mutated nucleotide causes an asparagine to lysine substitution at amino acid 37 of the encoded protein.  The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 1). 

Protein Function and Prediction

The F3 gene encodes the 294 amino acid Tissue factor (TF) that initiates blood coagulation by forming a complex with circulating factor VII or VIIa. This complex activates factors IX or X by specific limited protolysis. TF is a single-pass type I membrane protein with an extracellular domain at residues 29-251 and a cytoplasmic domain at residues 275-294. A WKS motif is located at amino acids 245-247 (Uniprot P20352). Homozygote mice for targeted null mutations exhibit impaired blood vessel development, retarded growth, and, in most cases, midgestational lethality. On a mixed background, some mutants survive to birth and appear to be normal.

The N37K change is located in the extracellular domain, and is predicted to be probably damaging by the PolyPhen program (see report).