GPER1
protein-codingG protein-coupled estrogen receptor 1, the group of G protein-coupled estrogen receptor
Gene summary
This gene encodes a multi-pass membrane protein that localizes to the endoplasmic reticulum and a member of the G-protein coupled receptor 1 family. This receptor binds estrogen and activates multiple downstream signaling pathways, leading to stimulation of adenylate cyclase and an increase in cyclic AMP levels, while also promoting intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estrogen. This receptor has been shown to play a role in diverse biological processes, including bone and nervous system development, metabolism, cognition, male fertility and uterine function. [provided by RefSeq, Aug 2017]
- CMKRL2
- GPR30
- GPER
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to GPER1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001098201.3. 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 | 1 | ||||
| missense | 59 | 2 | 1 | 62 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 0 | 0 | 59 | 3 | 1 | 63 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001091671.1 | 1 | MANE Select | |
| Ensembl | ENSP00000380277.3 | 1 | MANE Select | |
| RefSeq | NP_001035055.1 | 1 | Standard | |
| RefSeq | NP_001496.1 | 1 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| gper1 | Danio rerio | Structure: trunk Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Estrogen signaling pathway - Homo sapiens (human)
- GPCRs, Class A Rhodopsin-like
- Estrogen signaling pathway
- Signaling by GPCR
- Signal Transduction
Biological Process
- positive regulation of protein phosphorylation
- positive regulation of neurotransmitter secretion
- negative regulation of leukocyte activation
- inflammatory response
- cell cycle
Molecular Function
- chromatin binding
- G protein-coupled receptor activity
- steroid binding
- protein binding
- mineralocorticoid receptor activity
Cellular Component
- Golgi membrane
- nucleus
- nuclear envelope
- cytoplasm
- early endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000397092
- Coding exons
- 1
- Length
- 11608
- Individuals with no LoFs
- 125689
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 4
- Defined
- 125693
- p
- 0.0000159
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.11 | 218 | 269 | 0.810 | 0.0000196 | 2433 |
| Missense (PolyPhen) | 68 | 112.99 | 0.6018 | 1109 | ||
| Synonymous | -0.195 | 134 | 131 | 1.02 | 0.0000103 | 811 |
| Loss of Function | 2.07 | 1 | 6.83 | 0.147 | 2.94e-7 | 70 |
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 | 0.000055 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000028 | 0.000026 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: G-protein coupled estrogen receptor that binds to 17- beta-estradiol (E2) with high affinity, leading to rapid and transient activation of numerous intracellular signaling pathways. Stimulates cAMP production, calcium mobilization and tyrosine kinase Src inducing the release of heparin-bound epidermal growth factor (HB-EGF) and subsequent transactivation of the epidermal growth factor receptor (EGFR), activating downstream signaling pathways such as PI3K/Akt and ERK/MAPK. Mediates pleiotropic functions among others in the cardiovascular, endocrine, reproductive, immune and central nervous systems. Has a role in cardioprotection by reducing cardiac hypertrophy and perivascular fibrosis in a RAMP3-dependent manner. Regulates arterial blood pressure by stimulating vasodilation and reducing vascular smooth muscle and microvascular endothelial cell proliferation. Plays a role in blood glucose homeostasis contributing to the insulin secretion response by pancreatic beta cells. Triggers mitochondrial apoptosis during pachytene spermatocyte differentiation. Stimulates uterine epithelial cell proliferation. Enhances uterine contractility in response to oxytocin. Contributes to thymic atrophy by inducing apoptosis. Attenuates TNF-mediated endothelial expression of leukocyte adhesion molecules. Promotes neuritogenesis in developing hippocampal neurons. Plays a role in acute neuroprotection against NMDA- induced excitotoxic neuronal death. Increases firing activity and intracellular calcium oscillations in luteinizing hormone- releasing hormone (LHRH) neurons. Inhibits early osteoblast proliferation at growth plate during skeletal development. Inhibits mature adipocyte differentiation and lipid accumulation. Involved in the recruitment of beta-arrestin 2 ARRB2 at the plasma membrane in epithelial cells. Functions also as a receptor for aldosterone mediating rapid regulation of vascular contractibility through the PI3K/ERK signaling pathway. Involved in cancer progression regulation. Stimulates cancer-associated fibroblast (CAF) proliferation by a rapid genomic response through the EGFR/ERK transduction pathway. Associated with EGFR, may act as a transcription factor activating growth regulatory genes (c-fos, cyclin D1). Promotes integrin alpha-5/beta-1 and fibronectin (FN) matrix assembly in breast cancer cells. {ECO:0000269|PubMed:11043579, ECO:0000269|PubMed:15539556, ECO:0000269|PubMed:15705806, ECO:0000269|PubMed:19179659, ECO:0000269|PubMed:19342448, ECO:0000269|PubMed:20203690, ECO:0000269|PubMed:20551055, ECO:0000269|PubMed:21149639, ECO:0000269|PubMed:21242460, ECO:0000269|PubMed:21427217, ECO:0000269|PubMed:23135268, ECO:0000269|PubMed:23283935, ECO:0000269|PubMed:23285008, ECO:0000269|PubMed:23674134}.;
Recessive Scores
- pRec
- 0.134
Intolerance Scores
- RVIS EVS
- -0.29
- RVIS percentile EVS
- 33.42
Essentials
- Essential (CRISPR)
- N
- Essential (gene trap)
- N
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |