HRG

histidine rich glycoprotein, the group of Cystatins, type 4

Basic information

Region (hg38): 3:186660216-186678234

Links

ENSG00000113905 ∙ NCBI:3273 ∙ OMIM:142640 ∙ HGNC:5181 ∙ Uniprot:P04196 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (Strong), mode of inheritance: AD
• hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (Limited), mode of inheritance: AD
• hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Thrombophilia due to histidine-rich glycoprotein deficiency	AD	Hematologic	Individuals are at risk for thromboembolic events.and related sequelae, and knowledge may allow preventive measures as well as prompt treatment of manifestations	Hematologic	3689697; 8236132; 7769366; 8815595; 11057869
Elevated histidine-rich glycoprotein (HRG) has also been described as associated with risk of thromboembolism

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HRG gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HRG gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	7	2	10
missense			34	10	11	55
nonsense			1	1	1	3
start loss						0
frameshift			3			3
inframe indel			1	1	1	3
splice donor/acceptor (+/-2bp)						0
splice region					2	2
non coding					1	1
Total	0	0	40	19	16

Variants in HRG

This is a list of pathogenic ClinVar variants found in the HRG region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
3-186666079-G-A			Likely benign (Jul 01, 2024)
3-186666093-C-T		not specified	Uncertain significance (May 04, 2022)
3-186666103-C-A		Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Uncertain significance (-)
3-186666112-T-C		HRG-related disorder	Likely benign (Jun 04, 2019)
3-186666127-GA-G			Conflicting classifications of pathogenicity (Feb 01, 2021)
3-186666148-T-C			Uncertain significance (Oct 01, 2018)
3-186666156-G-A		HRG-related disorder • Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency • Thrombus	Conflicting classifications of pathogenicity (Feb 01, 2023)
3-186666156-G-T			Uncertain significance (Dec 01, 2023)
3-186666178-A-G		not specified	Likely benign (Aug 16, 2024)
3-186666198-C-T		not specified	Uncertain significance (Feb 28, 2024)
3-186666209-A-G		not specified	Uncertain significance (May 20, 2024)
3-186668924-G-T			Benign (Mar 03, 2015)
3-186668953-T-C		not specified	Uncertain significance (Dec 13, 2022)
3-186668955-C-T			Likely benign (Jun 21, 2017)
3-186668978-C-T		Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Uncertain significance (Jul 01, 2024)
3-186668987-C-G			Likely benign (Nov 01, 2022)
3-186669022-C-T		Familial early-onset deep venous thrombosis • Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Pathogenic/Likely pathogenic (May 16, 2018)
3-186669943-C-T			Benign (Apr 17, 2018)
3-186669944-G-A		not specified	Uncertain significance (Apr 12, 2022)
3-186669945-G-A		Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Pathogenic (Jan 01, 1998)
3-186670006-CT-C		Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency	Uncertain significance (Mar 29, 2024)
3-186671620-C-T		not specified	Benign (Aug 23, 2023)
3-186671624-C-A			Benign (Dec 09, 2017)
3-186671631-G-A		not specified	Uncertain significance (Feb 28, 2023)
3-186671646-A-G		not specified	Uncertain significance (May 09, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HRG	protein_coding	protein_coding	ENST00000232003	7	18025

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
5.89e-14	0.0155	125001	8	738	125747	0.00297

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.374	308	290	1.06	0.0000152	3481
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00891	0.00894
Ashkenazi Jewish	0.00	0.00
East Asian	0.000218	0.000217
Finnish	0.000647	0.000647
European (Non-Finnish)	0.000451	0.000448
Middle Eastern	0.000218	0.000217
South Asian	0.0168	0.0166
Other	0.00131	0.00130

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Dissolution of Fibrin Clot;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;Hemostasis (Consensus)

Recessive Scores

• pRec: 0.230

Intolerance Scores

• loftool: 0.956
• rvis_EVS: 3.67
• rvis_percentile_EVS: 99.55

Haploinsufficiency Scores

• pHI: 0.0837
• hipred: N
• hipred_score: 0.180

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0129

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Hrg
• Phenotype: homeostasis/metabolism phenotype; immune system phenotype; hematopoietic system phenotype

Gene ontology

• Biological process: angiogenesis;platelet degranulation;positive regulation of immune response to tumor cell;chemotaxis;negative regulation of cell adhesion;negative regulation of cell population proliferation;regulation of gene expression;regulation of platelet activation;negative regulation of lamellipodium assembly;negative regulation of endopeptidase activity;heme transport;negative regulation of angiogenesis;platelet activation;regulation of blood coagulation;negative regulation of cell growth;regulation of actin cytoskeleton organization;negative regulation of cell adhesion mediated by integrin;fibrinolysis;positive regulation of apoptotic process;regulation of protein complex assembly;negative regulation of blood vessel endothelial cell migration;regulation of peptidyl-tyrosine phosphorylation;defense response to fungus;cytolysis in other organism;positive regulation of focal adhesion assembly;negative regulation of fibrinolysis;antimicrobial humoral immune response mediated by antimicrobial peptide;negative regulation of vascular endothelial growth factor signaling pathway;positive regulation of blood vessel remodeling;negative regulation of endothelial cell chemotaxis
• Cellular component: extracellular region;plasma membrane;cell surface;platelet alpha granule lumen;endolysosome;collagen-containing extracellular matrix;extracellular exosome;blood microparticle
• Molecular function: serine-type endopeptidase inhibitor activity;cysteine-type endopeptidase inhibitor activity;signaling receptor binding;protein binding;heparin binding;zinc ion binding;immunoglobulin binding;heme binding;heparan sulfate proteoglycan binding;metal ion binding