SERPINF2
protein-codingserpin family F member 2, the group of Serpin peptidase inhibitors
Gene summary
This gene encodes a member of the serpin family of serine protease inhibitors. The protein is a major inhibitor of plasmin, which degrades fibrin and various other proteins. Consequently, the proper function of this gene has a major role in regulating the blood clotting pathway. Mutations in this gene result in alpha-2-plasmin inhibitor deficiency, which is characterized by severe hemorrhagic diathesis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]
- PLI
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009883
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009883
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0009883
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009883
Submitter: ClinGen
Alpha-2-plasmin inhibitor deficiency was first described in 1978 by Koie et al. (PMID: 82839), and is characterized by delayed bleeding after trauma, surgery and dental procedures. Bleeding in areas of high fibrinolytic activity is also common, such as menorrhagia and epistaxis. In 1987, the first variant was identified in patients by Holmes et al. (PMID: 2958938) establishing the relationship between SERPINF2 and autosomal recessive alpha-2-plasmin inhibitor deficiency. Patients with biallelic alpha-2-plasmin inhibitor deficiency may have severe bleeding manifestations, whereas heterozygotes may have milder bleeding tendencies or remain asymptomatic. At least 10 unique variants (including missense, nonsense, splicing and frameshift variants) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 9 publications (PMIDs: 31441040, 2958938, 17961166, 2496145, 2572590, 31577375, 29656168, 10959705, 12152655). Variants in this gene segregated with disease in 6 additional family members. Alpha-2-plasmin inhibitor acts as a primary and fast-acting inhibitor of plasmin; its major physiological role is to stabilize hemostatic plugs by inhibiting plasmin-mediated fibrinolysis that follows fibrin formation. The bleeding associated with a deficiency in alpha-2-plasmin inhibitor is because of the premature dissolution of hemostatic plugs before tissue and vessel repair. This gene-disease relationship is supported by its biochemical function in fibrinolysis (PMID: 134998), the functional alteration observed in patient cells which can be rescued with exogenous protein (PMID: 156196), and a knockout mouse model which recapitulates the alteration in fibrinolysis (PMID: 10090937). In summary, SERPINF2 is definitively associated with autosomal recessive alpha-2-plasmin inhibitor deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0009883
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009883
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009883
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Anti-fibrinolytic agents or FFP can be used to treat bleeding episodes, and to and prevent patients hemorrhagic complications in those who are undergoing surgical interventions; Intramedullary hematoma is also a common feature, and awareness of this potential manifestation can be beneficial in order to institute efficient treatment; Heterozygotes may also have (milder) manifestations
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SERPINF2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000934.4. 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 | 1 | 28 | 1 | 30 | ||
| missense | 1 | 61 | 15 | 1 | 78 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 2 | 2 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 1 | 63 | 43 | 2 | 112 |
Highest pathogenic variant AF is 0.0000030994413
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000925.2 | 9 | MANE Select | |
| Ensembl | ENSP00000402286.2 | 9 | MANE Select | |
| RefSeq | NP_001159392.1 | 9 | Standard | |
| RefSeq | NP_001159393.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Blood Clotting Cascade
- Dengue-2 Interactions with Complement and Coagulation Cascades
- Dengue-2 Interactions with Blood Clotting Cascade
- Complement and Coagulation Cascades
Biological Process
- regulation of blood vessel diameter by renin-angiotensin
- platelet degranulation
- acute-phase response
- response to organic substance
- negative regulation of plasminogen activation
Molecular Function
- protease binding
- endopeptidase inhibitor activity
- serine-type endopeptidase inhibitor activity
- protein binding
- protein homodimerization activity
Cellular Component
- extracellular region
- fibrinogen complex
- extracellular space
- cell surface
- platelet alpha granule lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000324015
- Coding exons
- 9
- Length
- 12433
- Individuals with no LoFs
- 125731
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125747
- p
- 0.0000636
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.23 | 229 | 288 | 0.796 | 0.0000181 | 3197 |
| Missense (PolyPhen) | 47 | 86.849 | 0.54117 | 1006 | ||
| Synonymous | -0.130 | 135 | 133 | 1.01 | 0.00000943 | 1008 |
| Loss of Function | 2.83 | 7 | 21.0 | 0.334 | 0.00000100 | 210 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00012 | rare |
| Latino/Admixed American | 0.000059 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000071 | 0.000044 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00065 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine protease inhibitor. The major targets of this inhibitor are plasmin and trypsin, but it also inactivates matriptase-3/TMPRSS7 and chymotrypsin. {ECO:0000269|PubMed:15853774}.;
- Disease
- DISEASE: Alpha-2-plasmin inhibitor deficiency (APLID) [MIM:262850]: An autosomal recessive disorder resulting in severe hemorrhagic diathesis. {ECO:0000269|PubMed:10583218, ECO:0000269|PubMed:2572590}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.535
Intolerance Scores
- LoFtool
- 0.0313
- RVIS EVS
- -0.78
- RVIS percentile EVS
- 13.05
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.920
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | Medium | High |