LGR4

leucine rich repeat containing G protein-coupled receptor 4, the group of G protein-coupled receptors, Class A orphans

Basic information

Region (hg38): 11:27365961-27472790

Previous symbols: [ "GPR48" ]

Links

ENSG00000205213 ∙ NCBI:55366 ∙ OMIM:606666 ∙ HGNC:13299 ∙ Uniprot:Q9BXB1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• delayed puberty, self-limited (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Delayed puberty, self-limited	AD	General	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	Endocrine	32493844

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the LGR4 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the LGR4 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				9	1	10
missense			54	3	3	60
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding				1	1	2
Total	0	0	54	13	5

Variants in LGR4

This is a list of pathogenic ClinVar variants found in the LGR4 region.

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

Position	Type	Phenotype	Significance	ClinVar
11-27367901-C-T		not specified	Uncertain significance (Mar 13, 2023)
11-27367937-G-A		not specified	Uncertain significance (Feb 16, 2023)
11-27367956-C-A		not specified	Uncertain significance (May 11, 2022)
11-27368012-G-T		not specified	Uncertain significance (Jul 26, 2022)
11-27368048-G-T		not specified	Uncertain significance (May 04, 2023)
11-27368082-A-C		not specified	Uncertain significance (Jul 12, 2022)
11-27368134-C-T		LGR4-related disorder	Likely benign (Jan 22, 2020)
11-27368148-C-G		not specified	Uncertain significance (May 16, 2022)
11-27368148-C-T		not specified	Uncertain significance (Dec 13, 2023)
11-27368154-C-T		not specified	Uncertain significance (Jan 03, 2024)
11-27368187-C-T		not specified	Uncertain significance (May 25, 2022)
11-27368192-T-C		Delayed puberty, self-limited	Pathogenic (Nov 10, 2021)
11-27368314-G-A			Likely benign (Jun 08, 2018)
11-27368343-C-G		not specified	Uncertain significance (Feb 22, 2023)
11-27368351-G-T		not specified	Uncertain significance (Aug 30, 2021)
11-27368431-C-T		LGR4-related disorder	Likely benign (Feb 25, 2019)
11-27368455-A-G			Likely benign (Oct 01, 2023)
11-27368475-C-T			Benign (Dec 31, 2019)
11-27368554-A-G		LGR4-related disorder	Likely benign (Jun 19, 2019)
11-27368556-C-T		not specified	Likely benign (Apr 24, 2024)
11-27368621-G-A		not specified	Uncertain significance (Jul 26, 2023)
11-27368652-G-A		not specified	Uncertain significance (Nov 18, 2023)
11-27368667-C-T		not specified	Uncertain significance (Dec 28, 2022)
11-27368673-T-C			Benign (Dec 31, 2019)
11-27368708-C-G		not specified	Uncertain significance (Oct 27, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
LGR4	protein_coding	protein_coding	ENST00000379214	18	106815

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.487	0.513	125720	0	28	125748	0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.22	388	461	0.841	0.0000228	6186
Missense in Polyphen		116	156.75	0.74003		2086
Synonymous	-0.866	194	179	1.08	0.00000938	1837
Loss of Function	4.64	9	41.1	0.219	0.00000199	545

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000207	0.000198
Ashkenazi Jewish	0.000256	0.0000992
East Asian	0.0000556	0.0000544
Finnish	0.000173	0.0000924
European (Non-Finnish)	0.000196	0.000158
Middle Eastern	0.0000556	0.0000544
South Asian	0.0000993	0.0000980
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Its function as activator of the Wnt signaling pathway is required for the development of various organs, including liver, kidney, intestine, bone, reproductive tract and eye. May also act as a receptor for norrin (NDP), such results however require additional confirmation in vivo. Required during spermatogenesis to activate the Wnt signaling pathway in peritubular myoid cells. Required for the maintenance of intestinal stem cells and Paneth cell differentiation in postnatal intestinal crypts. Acts as a regulator of bone formation and remodeling. Involved in kidney development; required for maintaining the ureteric bud in an undifferentiated state. Involved in the development of the anterior segment of the eye. Required during erythropoiesis. Also acts as a negative regulator of innate immunity by inhibiting TLR2/TLR4 associated pattern-recognition and proinflammatory cytokine production. Plays an important role in regulating the circadian rhythms of plasma lipids, partially through regulating the rhythmic expression of MTTP (By similarity). {ECO:0000250|UniProtKB:A2ARI4, ECO:0000269|PubMed:21693646, ECO:0000269|PubMed:21727895, ECO:0000269|PubMed:21909076, ECO:0000269|PubMed:22815884, ECO:0000269|PubMed:23444378, ECO:0000269|PubMed:23756652}.
• Disease: DISEASE: Osteoporosis (OSTEOP) [MIM:166710]: A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. {ECO:0000269|PubMed:23644456}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry. A LGR4 nonsense mutation creating a stop codon after position 126 (c.376C>T) is strongly associated with low bone mineral density and osteoporotic fractures (PubMed:23644456). This mutation probably causes degradation of the transcript by nonsense-mediated decay (NMD). The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer (PubMed:23644456). {ECO:0000269|PubMed:23644456}.
• Pathway: Signaling by WNT;Signal Transduction;Regulation of FZD by ubiquitination;TCF dependent signaling in response to WNT (Consensus)

Recessive Scores

• pRec: 0.130

Intolerance Scores

• loftool: 0.391
• rvis_EVS: -0.26
• rvis_percentile_EVS: 34.88

Haploinsufficiency Scores

• pHI: 0.467
• hipred: Y
• hipred_score: 0.595
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.228

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Lgr4
• Phenotype: renal/urinary system phenotype; immune system phenotype; vision/eye phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); liver/biliary system phenotype; embryo phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan)

Gene ontology

• Biological process: osteoblast differentiation;hair follicle development;adenylate cyclase-activating G protein-coupled receptor signaling pathway;activation of adenylate cyclase activity;spermatogenesis;hormone-mediated signaling pathway;bone mineralization;male genitalia development;circadian regulation of gene expression;negative regulation of toll-like receptor signaling pathway;intestinal stem cell homeostasis;innate immune response;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;bone remodeling;digestive tract development;negative regulation of cytokine secretion;canonical Wnt signaling pathway involved in metanephric kidney development;cell differentiation involved in metanephros development;metanephric glomerulus development;metanephric nephron tubule morphogenesis;positive regulation of branching involved in ureteric bud morphogenesis;positive regulation of canonical Wnt signaling pathway;negative regulation of cold-induced thermogenesis;epithelial cell proliferation involved in renal tubule morphogenesis
• Cellular component: plasma membrane;integral component of plasma membrane
• Molecular function: transmembrane signaling receptor activity;G protein-coupled receptor activity;protein binding;G protein-coupled peptide receptor activity;protein-hormone receptor activity