GP9

protein-coding

glycoprotein IX platelet, the group of CD molecules

Gene summary

This gene encodes a small membrane glycoprotein found on the surface of human platelets. It forms a 1-to-1 noncovalent complex with glycoprotein Ib, a platelet surface membrane glycoprotein complex that functions as a receptor for von Willebrand factor. The complete receptor complex includes noncovalent association of the alpha and beta subunits with the protein encoded by this gene and platelet glycoprotein V. Defects in this gene are a cause of Bernard-Soulier syndrome, also known as giant platelet disease. These patients have unusually large platelets and have a clinical bleeding tendency. [provided by RefSeq, Oct 2008]

MANE transcript

NM_000174.5

Inheritance

AR, AD

ClinVar variants

P:27U:56B:72

Top phenotype

Bernard-Soulier syndrome, type C

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr3:129,060,779-129,062,406

External References & Databases

Ensembl (ENSG00000169704)

Transcript & Mutation Effects

hg38 • Region Span ~1.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bernard-Soulier syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: PanelApp Australia

Bernard-Soulier syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: ClinGen

GP9 was first reported in relation to autosomal recessive Bernard-Soulier syndrome in 1993 Wright SD, et al., 1993, PMID: 8481514). At least 32 unique variants (primarily missense, with some nonsense, and frameshifts) have been reported in humans. The unifying feature of all of the mutations is the ability of the mutation to disrupt the assembly and/or function of a surface-expressed GP Ib-IX-V complex. How individual mutations affect complex assembly or surface expression can be variable. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 36 probands in 12 publications (PMIDs: 8481514, 23143686, 9432024, 21699652, 21173099, 21113250, 9886312, 12100158, 10583255, 16916536, 15609295, 23995613). Variants in this gene segregated with disease in 6 additional family members. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. This gene-disease association is supported by its reduced expression in patient cells (PMID: 9432024), its protein interactions with GP1BB (PMID: 808914), functional alteration in non-patient cells (PMID: 10527407, PMID: 8608225), and a knock-out animal model (PMID: 28650483). In summary, GP9 is definitively associated with autosomal recessive Bernard-Soulier syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Bernard-Soulier syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009276

Submitter: Orphanet

Bernard-Soulier syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009276

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Bernard-Soulier syndrome, type CAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Preventive measures (eg, in the case of surgery) and treatment of bleeding episodes can be beneficial; Specific medications (eg, certain anesthetics) that interfere with platelet function should be avoided

Refs: 18116504; 14081293; 6019024; 1901273; 8481514; 9616133; 16268478; 17109744; 21173099; 21699652

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GP9 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 105

Bernard Soulier syndromeTotal: 57

Inborn genetic diseasesTotal: 23

not specifiedTotal: 22

GP9-related disorderTotal: 14

Bernard-Soulier syndrome type CTotal: 6

GP9-related disordersTotal: 6

MacrothrombocytopeniaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000174.5. 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				61 clinvar	2 clinvar	63
missense	4 clinvar	10 clinvar	55 clinvar	6 clinvar	3 clinvar	78
nonsense		4 clinvar				4
start loss	1 clinvar		1 clinvar			2
frameshift	3 clinvar	5 clinvar				8
splice donor/acceptor (+/-2bp)						0
Total	8	19	56	67	5	155

Highest pathogenic variant AF is 0.0007009007

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000174.5	RefSeq	NP_000165.1	1	MANE Select
ENST00000307395.5	Ensembl	ENSP00000303942.4	1	MANE Select
ENST00000900754.1	Ensembl	ENSP00000570813.1	1	Standard
ENST00000900754.2	Ensembl	ENSP00000570813.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet activation - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Hematopoietic cell lineage - Homo sapiens (human)
Platelet Aggregation Inhibitor Pathway, Pharmacodynamics
Hematopoietic Stem Cell Differentiation

Biological Process

cell adhesion
blood coagulation
blood coagulation, intrinsic pathway
platelet activation

Molecular Function

protein binding

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307395
Coding exons: 1
Length: 1640
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.163	109	114	0.957	0.00000776	1080
Missense (PolyPhen)		27	31.977	0.84436		369
Synonymous	-0.465	63	58.5	1.08	0.00000419	414
Loss of Function	1.22	0	1.72	0.00	7.44e-8	16

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The GPIb-V-IX complex functions as the vWF receptor and mediates vWF-dependent platelet adhesion to blood vessels. The adhesion of platelets to injured vascular surfaces in the arterial circulation is a critical initiating event in hemostasis. GP-IX may provide for membrane insertion and orientation of GP-Ib.;
Disease: DISEASE: Bernard-Soulier syndrome (BSS) [MIM:231200]: A coagulation disorder characterized by a prolonged bleeding time, unusually large platelets, thrombocytopenia, and impaired prothrombin consumption. {ECO:0000269|PubMed:10583255, ECO:0000269|PubMed:11167791, ECO:0000269|PubMed:11758225, ECO:0000269|PubMed:12100158, ECO:0000269|PubMed:8481514, ECO:0000269|PubMed:9163595, ECO:0000269|PubMed:9886312}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.227

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0845

Gene Damage Prediction

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