HRG
protein-codinghistidine rich glycoprotein, the group of Cystatins, type 4
Gene summary
This histidine-rich glycoprotein contains two cystatin-like domains and is located in plasma and platelets. The physiological function has not been determined but it is known that the protein binds heme, dyes and divalent metal ions. The encoded protein also has a peptide that displays antimicrobial activity against C. albicans, E. coli, S. aureus, P. aeruginosa, and E. faecalis. It can inhibit rosette formation and interacts with heparin, thrombospondin and plasminogen. Two of the protein's effects, the inhibition of fibrinolysis and the reduction of inhibition of coagulation, indicate a potential prothrombotic effect. Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels. [provided by RefSeq, Nov 2014]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~18.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013143
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013143
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013143
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0013143
Submitter: ClinGen
HRG was first associated with hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency in 1998 (PMID: 9414276). The spectrum of coagulation disorders currently reported in HRG-deficient patients includes transverse sinus thrombosis, dual arteriovenous fistula at sites of previous thrombosis and deep vein thrombosis. This association was made using case-level data and experimental evidence. At least 3 unique missense variants have been reported in humans in at least 3 probands in 3 publications (PMID: 9414276, 29108964, 11057869). Variants in this gene segregated with thrombosis in 3 additional family members and segregated with HRG deficiency in 8 family members. Two of the HRG variant proteins were found to be only partially secreted and haploinsufficiency is therefore proposed as a pathogenic mechanism (PMID: 9414276). It is noteworthy that multiple thrombophilia families have elevated levels of plasma HRG, as reported in several studies (Castaman et al., 1993), which seems contradictory to the phenomenon observed in HRG-deficient families. One possible explanation is that HRG mutations lead to decreased levels of plasma HRG, whereas HRG mutations negative patients have compensatory elevated plasma secondary to thromboembolism events. A role of HRG in hemostasis has been repeatedly proposed based on the observation that HRG binds several components of the coagulation and fibrinolysis cascades. Experimental evidence supporting the association with thrombophilia includes the biochemical functions of inactivating platelet thrombospondin, a strong promoter of platelet aggregation (PMID: 6690483) and inhibiting autoactivation of factor XII and factor XIIa–mediated activation of factor XI, thus modulating the intrinsic pathway of coagulation (PMID: 21304106), as confirmed in HRG-deficient plasma (PMID: 21304106). Additionally, a null mouse model has been shown to have shortened prothrombin time and tail bleeding time in the absence of HRG (PMID: 15869579), as well as accelerated carotid artery occlusion (PMID: 25691157), due to the role of HRG as a regulator of the intrinsic pathway (PMIDs: 25691157, 34474475). Administration of human HRG abrogated the effects on prothrombin time and carotid artery occlusion. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this association definitively, no convincing contradictory evidence has emerged. This classification was originally approved by the ClinGen Hemostasis Thrombosis Gene Curation Expert Panel on December 15, 2021. This gene-disease relationship was reevaluated on February 5, 2024. As a result of this reevaluation, the classification did not change.
Clinical Genomic Database (CGD)
Manifestation: Hematologic
Intervention: Hematologic
Rationale: Individuals are at risk for thromboembolic events.and related sequelae, and knowledge may allow preventive measures as well as prompt treatment of manifestations
Comments: Elevated histidine-rich glycoprotein (HRG) has also been described as associated with risk of thromboembolism
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HRG variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000412.5. 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 | 12 | 4 | 19 | ||
| missense | 1 | 1 | 88 | 24 | 4 | 118 |
| nonsense | 1 | 2 | 1 | 4 | ||
| start loss | 0 | |||||
| frameshift | 5 | 1 | 6 | |||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 97 | 39 | 9 | 147 |
Highest pathogenic variant AF is 0.0000043611967
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000403.1 | 7 | MANE Select | |
| Ensembl | ENSP00000232003.4 | 7 | MANE Select | |
| Ensembl | ENSP00000557916.1 | 7 | Standard | |
| Ensembl | ENSP00000557917.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Dissolution of Fibrin Clot
- Platelet degranulation
- Response to elevated platelet cytosolic Ca2+
- Platelet activation, signaling and aggregation
- Hemostasis
Biological Process
- angiogenesis
- platelet degranulation
- positive regulation of immune response to tumor cell
- chemotaxis
- negative regulation of cell adhesion
Molecular Function
- serine-type endopeptidase inhibitor activity
- cysteine-type endopeptidase inhibitor activity
- signaling receptor binding
- protein binding
- heparin binding
Cellular Component
- extracellular region
- plasma membrane
- cell surface
- platelet alpha granule lumen
- endolysosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000232003
- Coding exons
- 7
- Length
- 18025
- Individuals with no LoFs
- 125001
- Homozygous LoFs
- 8
- Heterozygous LoFs
- 738
- Defined
- 125747
- p
- 0.00297
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.374 | 308 | 290 | 1.06 | 0.0000152 | 3481 |
| Missense (PolyPhen) | 25 | 25.845 | 0.96732 | 296 | ||
| Synonymous | -0.0122 | 111 | 111 | 1.00 | 0.00000605 | 1001 |
| Loss of Function | -0.122 | 20 | 19.4 | 1.03 | 0.00000117 | 224 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0078 | 0.0078 | notable |
| Latino/Admixed American | 0.0011 | 0.0011 | notable |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00022 | 0.00022 | rare |
| Finnish | 0.00065 | 0.00065 | rare |
| European (Non-Finnish) | 0.00045 | 0.00045 | rare |
| South Asian | 0.017 | 0.017 | notable |
| Other | 0.0013 | 0.0013 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis. {ECO:0000269|PubMed:11134179, ECO:0000269|PubMed:12235005, ECO:0000269|PubMed:14744774, ECO:0000269|PubMed:15220341, ECO:0000269|PubMed:15313924, ECO:0000269|PubMed:16436387, ECO:0000269|PubMed:16489009, ECO:0000269|PubMed:19285951, ECO:0000269|PubMed:19535045, ECO:0000269|PubMed:19712047, ECO:0000269|PubMed:19903770, ECO:0000269|PubMed:20573803, ECO:0000269|PubMed:21215706, ECO:0000269|PubMed:21304106}.;
- Disease
- DISEASE: Thrombophilia due to histidine-rich glycoprotein deficiency (THPH11) [MIM:613116]: A hemostatic disorder characterized by a tendency to thrombosis. {ECO:0000269|PubMed:11057869, ECO:0000269|PubMed:9414276}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.230
Intolerance Scores
- LoFtool
- 0.956
- RVIS EVS
- 3.67
- RVIS percentile EVS
- 99.55
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.0129
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |