SERPIND1
protein-codingserpin family D member 1, the group of Serpin peptidase inhibitors
Gene summary
This gene belongs to the serpin gene superfamily. Serpins play roles in many processes including inflammation, blood clotting, and cancer metastasis. Members of this family have highly conserved secondary structures with a reactive center loop that interacts with the protease active site to inhibit protease activity. This gene encodes a plasma serine protease that functions as a thrombin and chymotrypsin inhibitor. The protein is activated by heparin, dermatan sulfate, and glycosaminoglycans. Allelic variations in this gene are associated with heparin cofactor II deficiency. [provided by RefSeq, Jul 2015]
- HCF2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~13.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: Unknown
Disease ID:MONDO:0012876
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0012876
Submitter: ClinGen
Heparin cofactor II (HCII) deficiency was first associated with thrombosis in 1985 by Tran et al. (PMID: 2863444). HCII is a serine protease inhibitor in plasma that rapidly inhibits thrombin in the presence of dermatan sulfate or heparin. However, HCII deficiency may represent only a modest risk of thrombosis, becoming clinically manifest only when additional inherited or acquired thrombogenic conditions are present. In 1987, Andersson et al. (PMID: 2443998) established an autosomal dominant mode of inheritance, which affected individuals having half the normal amount of HCF II. These individuals were molecularly characterized by Blinder et al. (PMID: 2647747) in 1989. At least 8 unique variants (including missense 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 7 publications (PMIDs: 8902986, 2647747, 15337701, 31064749, 11204559, 8562924, 29296762). Variants in this gene segregated with HCII deficiency in 23 additional family members. This gene-disease relationship is supported by its biochemical function of inhibiting thrombin (PMID: 6895893), the alteration of expression (PMID: 2863444) and function (PMID: 2647747) observed in patients, and multiple mouse models which recapitulate the HCII deficiency and increased susceptibility to induced thrombosis but can be rescued with human HCII (PMID: 17549254, 11805133). In summary, SERPIND1 is definitively associated with autosomal dominant heparin cofactor II deficiency.
Inheritance Pattern: AD
Disease ID:MONDO:0012876
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0012876
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Individuals may be at higher risk for thrombophilia, though data are controversial, and may be clinically relevant only in the presence of another thrombophilia-related variant
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SERPIND1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000185.4. 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 | 17 | 2 | 20 | ||
| missense | 1 | 65 | 14 | 2 | 82 | |
| nonsense | 1 | 2 | 3 | |||
| start loss | 0 | |||||
| frameshift | 2 | 3 | 5 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 3 | 1 | 72 | 31 | 4 | 111 |
Highest pathogenic variant AF is 0.000004337083
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000176.2 | 4 | MANE Select | |
| Ensembl | ENSP00000215727.5 | 4 | MANE Select | |
| Ensembl | ENSP00000384050.1 | 4 | Standard | |
| Ensembl | ENSP00000384050.1 | 4 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Complement and coagulation cascades - Homo sapiens (human)
- Dengue-2 Interactions with Complement and Coagulation Cascades
- Complement and Coagulation Cascades
- Post-translational protein phosphorylation
- Post-translational protein modification
Biological Process
- chemotaxis
- blood coagulation
- negative regulation of endopeptidase activity
- post-translational protein modification
- cellular protein metabolic process
Molecular Function
- endopeptidase inhibitor activity
- serine-type endopeptidase inhibitor activity
- heparin binding
Cellular Component
- extracellular region
- extracellular space
- endoplasmic reticulum lumen
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000215727
- Coding exons
- 4
- Length
- 13842
- Individuals with no LoFs
- 125683
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 65
- Defined
- 125748
- p
- 0.000258
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0568 | 288 | 285 | 1.01 | 0.0000173 | 3352 |
| Missense (PolyPhen) | 108 | 110.59 | 0.97659 | 1346 | ||
| Synonymous | -0.899 | 127 | 115 | 1.11 | 0.00000773 | 953 |
| Loss of Function | 0.0923 | 15 | 15.4 | 0.975 | 8.20e-7 | 181 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00062 | 0.00062 | rare |
| Latino/Admixed American | 0.00017 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00033 | 0.00033 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00027 | 0.00027 | rare |
| South Asian | 0.00023 | 0.00023 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Thrombin inhibitor activated by the glycosaminoglycans, heparin or dermatan sulfate. In the presence of the latter, HC-II becomes the predominant thrombin inhibitor in place of antithrombin III (AT-III). Also inhibits chymotrypsin, but in a glycosaminoglycan-independent manner. {ECO:0000269|PubMed:1939083}.;
- Disease
- DISEASE: Thrombophilia due to heparin cofactor 2 deficiency (THPH10) [MIM:612356]: A hemostatic disorder characterized by a tendency to recurrent thrombosis. {ECO:0000269|PubMed:10391209, ECO:0000269|PubMed:11204559, ECO:0000269|PubMed:15337701, ECO:0000269|PubMed:2647747}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.267
Intolerance Scores
- LoFtool
- 0.168
- RVIS EVS
- 0.56
- RVIS percentile EVS
- 81.63
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.998
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |