SERPINE1

protein-coding

serpin family E member 1, the group of Serpin peptidase inhibitors

Gene summary

This gene encodes a member of the serine proteinase inhibitor (serpin) superfamily. This member is the principal inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA), and hence is an inhibitor of fibrinolysis. The protein also functions as a component of innate antiviral immunity. Defects in this gene are the cause of plasminogen activator inhibitor-1 deficiency (PAI-1 deficiency), and high concentrations of the gene product are associated with thrombophilia. [provided by RefSeq, Aug 2020]

Previous symbols:

PLANH1
PAI1

MANE transcript

NM_000602.5

Inheritance

AR, SD

ClinVar variants

P:1U:61B:12

Top phenotype

Plasminogen activator inhibitor-1 deficiency

gnomAD constraint

pLI —, LoF o/e 0.33

Max pathogenic AF

—

Genomic locus

chr7:101,127,104-101,139,247

External References & Databases

Ensembl (ENSG00000106366)

Transcript & Mutation Effects

hg38 • Region Span ~12.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital plasminogen activator inhibitor type 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013227

Submitter: ClinGen

SERPINE1 was first reported in relation to autosomal recessive complete plasminogen activator inhibitor 1 (PAI-1) deficiency in 1992 (Fay et al, PMID: 1435917), however partial PAI-1 deficiency was described in 1989 and 1991 (Schleef et al, PMID: 2496147; Dieval et al, PMID: 1899347). PAI-1 is encoded by SERPINE1, a serpin protease inhibitor. Complete plasminogen activator inhibitor 1 deficiency is characterized by moderate bleeding, however life-threatening bleeding events have been documented. Most commonly, bleeding is delayed after trauma or surgery; spontaneous bleeding does not occur. Evidence supporting this gene-disease curation includes case-level data, segregation data, and experimental data. Summary of Case Level Data (9.0 points): Four unique variants have been reported in humans; three frame shift variants and a missense variant. Variants in this gene have been reported in at least 3 probands in 3 publications (PMID: 9207454; 21486382; 28229167; 32278876). Variants in this gene segregated with disease in 6 additional family members. Summary of Segregation (LOD Score) (1.5 points): Using candidate gene sequencing, 7 affected individuals and 18 unaffected individuals from an Old Order Amish community were included in the LOD score (PMID: 1435917; 9207454). Summary of Experimental Data (4 points): This gene disease relationship is supported by biochemical function (PMID: 1435917), Expression (PMID: 1435917), and model systems (PMID: 9529269) experiments. In summary, SERPINE1 is definitively associated with autosomal recessive complete plasminogen activator inhibitor 1 (PAI-1) deficiency. This has been repeatedly demonstrated in both the research and the clinical diagnostic settings and has been upheld over time. This gene-disease pair was originally approved by the HT GCEP in January of 2021. Subsequent curation was completed in October of 2023 using Gene-Disease Validity Standard Operating Procedures, Version 9.

congenital plasminogen activator inhibitor type 1 deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013227

Submitter: Ambry Genetics

congenital plasminogen activator inhibitor type 1 deficiencySTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0013227

Submitter: PanelApp Australia

congenital plasminogen activator inhibitor type 1 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013227

Submitter: Orphanet

congenital plasminogen activator inhibitor type 1 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013227

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Plasminogen activator inhibitor-1 deficiencyAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals are susceptible to bleeding related to situations such as traumatic injury or surgery, and females manifest with menorrhagia, and precautions may be helpful to avoid severe sequelae; Medical treatment (eg, with fibrinolysis inhibitors) have been reported as beneficial in the prevention and treatment of bleeding episodes

Refs: 2496147; 1435917; 9207454; 10754381; 15650551; 20664190; 21486382

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINE1 variants in ClinVar

8 Conditions Cataloged

not specifiedTotal: 40

Congenital plasminogen activator inhibitor type 1 deficiencyTotal: 30

not providedTotal: 14

SERPINE1-related disorderTotal: 4

HemorrhageTotal: 2

Abnormal bleedingTotal: 1

ThrombusTotal: 1

Gastrointestinal hemorrhageTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000602.5. 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			3 clinvar	6 clinvar	2 clinvar	11
missense			53 clinvar	3 clinvar	1 clinvar	57
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar		1 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	0	61	9	3	74

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000602.5	RefSeq	NP_000593.1	8	MANE Select
ENST00000223095.5	Ensembl	ENSP00000223095.4	8	MANE Select
NM_001386456.1	RefSeq	NP_001373385.1	8	Standard
NM_001386457.1	RefSeq	NP_001373386.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Complement and coagulation cascades - Homo sapiens (human)
AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)
HIF-1 signaling pathway - Homo sapiens (human)
p53 signaling pathway - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)

Biological Process

chronological cell aging
angiogenesis
platelet degranulation
circadian rhythm
regulation of signaling receptor activity

Molecular Function

protease binding
serine-type endopeptidase inhibitor activity
signaling receptor binding
protein binding

Cellular Component

extracellular region
extracellular space
plasma membrane
platelet alpha granule lumen
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000223095
Coding exons: 8
Length: 12178
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.453	213	232	0.916	0.0000149	2646
Missense (PolyPhen)		59	89.319	0.66055		1042
Synonymous	-0.0577	98	97.3	1.01	0.00000697	808
Loss of Function	2.45	5	15.4	0.326	6.77e-7	189

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.000062	0.000062	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine protease inhibitor. Inhibits TMPRSS7 (PubMed:15853774). Is a primary inhibitor of tissue-type plasminogen activator (PLAT) and urokinase-type plasminogen activator (PLAU). As PLAT inhibitor, it is required for fibrinolysis down-regulation and is responsible for the controlled degradation of blood clots (PubMed:8481516, PubMed:9207454, PubMed:17912461). As PLAU inhibitor, it is involved in the regulation of cell adhesion and spreading (PubMed:9175705). Acts as a regulator of cell migration, independently of its role as protease inhibitor (PubMed:15001579, PubMed:9168821). It is required for stimulation of keratinocyte migration during cutaneous injury repair (PubMed:18386027). It is involved in cellular and replicative senescence (PubMed:16862142). Plays a role in alveolar type 2 cells senescence in the lung (By similarity). Is involved in the regulation of cementogenic differentiation of periodontal ligament stem cells, and regulates odontoblast differentiation and dentin formation during odontogenesis (PubMed:25808697, PubMed:27046084). {ECO:0000250|UniProtKB:P22777, ECO:0000269|PubMed:15001579, ECO:0000269|PubMed:15853774, ECO:0000269|PubMed:16862142, ECO:0000269|PubMed:17912461, ECO:0000269|PubMed:18386027, ECO:0000269|PubMed:25808697, ECO:0000269|PubMed:27046084, ECO:0000269|PubMed:8481516, ECO:0000269|PubMed:9168821, ECO:0000269|PubMed:9175705, ECO:0000269|PubMed:9207454}.;
Disease: DISEASE: Plasminogen activator inhibitor-1 deficiency (PAI-1D) [MIM:613329]: A hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of plasminogen activator inhibitor-1, which inhibits tissue and urinary activators of plasminogen. {ECO:0000269|PubMed:8481516, ECO:0000269|PubMed:9207454}. Note=The disease is caused by mutations affecting the gene represented in this entry. A rare PAI-1D mutation resulting in a frameshift and protein truncation has been found in an Old Order Amish community. Homozygous mutation carriers suffer from episodes of major hemorrhage, while heterozygous carriers do not manifest abnormal bleeding (PubMed:9207454). Heterozygosity for the mutation is associated with longer leukocyte telomere length, lower fasting insulin levels, lower prevalence of diabetes mellitus, and a longer life span (PubMed:29152572). {ECO:0000269|PubMed:29152572, ECO:0000269|PubMed:9207454}.;

Recessive Scores

pRec: 0.869

Intolerance Scores

LoFtool: 0.170
RVIS EVS: -0.27
RVIS percentile EVS: 34.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.948

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium