NR3C1

nuclear receptor subfamily 3 group C member 1, the group of Nuclear receptor subfamily 3 group C

Basic information

Region (hg38): 5:143277930-143435512

Previous symbols: [ "GRL" ]

Links

ENSG00000113580 ∙ NCBI:2908 ∙ OMIM:138040 ∙ HGNC:7978 ∙ Uniprot:P04150 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• glucocorticoid resistance (Strong), mode of inheritance: AD
• glucocorticoid resistance (Strong), mode of inheritance: AD
• glucocorticoid resistance (Supportive), mode of inheritance: AD
• glucocorticoid resistance (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Glucocorticoid resistance	AD/AR	Endocrine	Treatment focuses on suppression of excess ACTH production, and may include high-dose mineralocorticoid-sparing synthetic glucocorticoids; Individuals may also display other endocrinologic anomalies (eg, growth hormone deficiency), and surveillance and prompt recognition and treatment may be beneficial	Endocrine	186477; 6841559; 2996089; 1704018; 8445027; 8863343; 11701741; 11589680; 11932321; 12050230; 12754700; 14764810; 15769988; 16449337; 17635946; 18319312; 19694013; 19933394; 23076843

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NR3C1 gene.

• Glucocorticoid resistance (118 variants)
• not provided (49 variants)
• Inborn genetic diseases (7 variants)
• not specified (3 variants)
• NR3C1-related condition (1 variants)
• Glucocorticoid resistance, relative (1 variants)
• GLUCOCORTICOID RECEPTOR POLYMORPHISM (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NR3C1 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			2	12	6	20
missense		1	37	7	1	46
nonsense	1					1
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)		1				1
splice region			3	4		7
non coding			70	8	4	82
Total	1	2	109	27	11

Highest pathogenic variant AF is 0.00000657

Variants in NR3C1

This is a list of pathogenic ClinVar variants found in the NR3C1 region.

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

Position	Type	Phenotype	Significance	ClinVar
5-143277952-T-A		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278012-G-A		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278021-G-A		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278043-C-T		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278056-T-C		Glucocorticoid resistance	Benign (Mar 06, 2018)
5-143278129-C-CT		Glucocorticoid resistance	Uncertain significance (Jun 14, 2016)
5-143278204-G-C		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278309-A-G		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278339-C-T		Glucocorticoid resistance	Likely benign (Jan 12, 2018)
5-143278423-A-G		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278458-C-G		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278483-G-C		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278506-A-C		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278511-C-T		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278559-C-A		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278570-C-G		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278589-C-A		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278591-C-A		Glucocorticoid resistance	Benign (Jan 12, 2018)
5-143278630-C-T		Glucocorticoid resistance	Uncertain significance (Apr 06, 2018)
5-143278736-G-A		Glucocorticoid resistance	Likely benign (Jan 13, 2018)
5-143278812-C-T		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278813-G-A		Glucocorticoid resistance	Likely benign (Jan 12, 2018)
5-143278843-C-G		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)
5-143278886-T-C		Glucocorticoid resistance	Uncertain significance (Jan 13, 2018)
5-143278933-C-T		Glucocorticoid resistance	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NR3C1	protein_coding	protein_coding	ENST00000231509	8	157582

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.970	0.0304	125740	0	8	125748	0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.84	293	396	0.740	0.0000198	5073
Missense in Polyphen		63	153.41	0.41066		2015
Synonymous	-0.172	153	150	1.02	0.00000809	1525
Loss of Function	4.50	5	32.9	0.152	0.00000176	416

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.0000352	0.0000352
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for glucocorticoids (GC) (PubMed:27120390). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Involved in chromatin remodeling (PubMed:9590696). Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay (PubMed:25775514). Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity). {ECO:0000250|UniProtKB:P06537, ECO:0000269|PubMed:25775514, ECO:0000269|PubMed:27120390, ECO:0000269|PubMed:9590696}.; FUNCTION: Isoform Beta: Acts as a dominant negative inhibitor of isoform Alpha (PubMed:7769088, PubMed:8621628, PubMed:20484466). Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed (PubMed:19248771, PubMed:26711253). Loses this transcription modulator function on its own (PubMed:20484466). Has no hormone-binding activity (PubMed:8621628). May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity). Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner (PubMed:26711253). Directly regulates STAT1 expression in isoform Alpha-independent manner (PubMed:26711253). {ECO:0000250|UniProtKB:P06537, ECO:0000269|PubMed:19248771, ECO:0000269|PubMed:20484466, ECO:0000269|PubMed:26711253, ECO:0000269|PubMed:7769088, ECO:0000269|PubMed:8621628}.; FUNCTION: Isoform GR-P: Increases activity of isoform Alpha. {ECO:0000269|PubMed:11358809}.; FUNCTION: Isoform 10: Has transcriptional activation activity. {ECO:0000269|PubMed:20484466}.; FUNCTION: Isoform Alpha-C2: Has transcriptional activation activity. {ECO:0000269|PubMed:15866175}.; FUNCTION: Isoform Alpha-D1: Has transcriptional activation activity. {ECO:0000269|PubMed:15866175}.; FUNCTION: Isoform Alpha-D3: Has lowest transcriptional activation activity of all isoforms created by alternative initiation (PubMed:15866175, PubMed:23820903). Has transcriptional repression activity (PubMed:23303127). {ECO:0000269|PubMed:15866175, ECO:0000269|PubMed:23303127, ECO:0000269|PubMed:23820903}.
• Disease: DISEASE: Glucocorticoid resistance, generalized (GCCR) [MIM:615962]: An autosomal dominant disease characterized by increased plasma cortisol concentration and high urinary free cortisol, resistance to adrenal suppression by dexamethasone, and the absence of Cushing syndrome typical signs. Clinical features include hypoglycemia, hypertension, metabolic alkalosis, chronic fatigue and profound anxiety. {ECO:0000269|PubMed:11589680, ECO:0000269|PubMed:11701741, ECO:0000269|PubMed:12050230, ECO:0000269|PubMed:15769988, ECO:0000269|PubMed:1704018, ECO:0000269|PubMed:17635946, ECO:0000269|PubMed:20335448, ECO:0000269|PubMed:21362280, ECO:0000269|PubMed:23426617, ECO:0000269|PubMed:24483153, ECO:0000269|PubMed:26031419, ECO:0000269|PubMed:26541474, ECO:0000269|PubMed:27120390, ECO:0000269|PubMed:7683692}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Neuroactive ligand-receptor interaction - Homo sapiens (human);Glucocorticoid Pathway (Peripheral Tissue), Pharmacodynamics;Prednisolone Metabolism Pathway;Prednisolone Action Pathway;NHR;TGF-Ncore;Nuclear Receptors;White fat cell differentiation;Adipogenesis;Endoderm Differentiation;Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Transcription factor regulation in adipogenesis;White fat cell differentiation;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Serotonin Receptor 4-6-7 and NR3C Signaling;Signaling by PTK6;Transcriptional regulation by RUNX2;Signal Transduction;Gene expression (Transcription);visceral fat deposits and the metabolic syndrome;rna polymerase iii transcription;corticosteroids and cardioprotection;the information processing pathway at the ifn beta enhancer;nfkb activation by nontypeable hemophilus influenzae;carm1 and regulation of the estrogen receptor;Generic Transcription Pathway;HSP90 chaperone cycle for steroid hormone receptors (SHR);Cellular responses to stress;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;PTK6 Expression;Cellular responses to external stimuli;Signaling events mediated by HDAC Class II;Glucocorticoid receptor regulatory network;IL2;Signaling by Non-Receptor Tyrosine Kinases;chromatin remodeling by hswi/snf atp-dependent complexes;AP-1 transcription factor network;Regulation of Androgen receptor activity;FOXA2 and FOXA3 transcription factor networks;Regulation of nuclear SMAD2/3 signaling;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.930

Intolerance Scores

• loftool: 0.0657
• rvis_EVS: -0.16
• rvis_percentile_EVS: 42.16

Haploinsufficiency Scores

• pHI: 0.995
• hipred: Y
• hipred_score: 0.743
• ghis: 0.511

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nr3c1
• 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); digestive/alimentary phenotype; skeleton phenotype; no phenotypic analysis (no description of morphological, physiological or behavioral information presented); immune system phenotype; respiratory system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms 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); normal 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); hematopoietic system phenotype; 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); growth/size/body region phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism 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)

Zebrafish Information Network

• Gene name: nr3c1
• Affected structure: hematopoietic multipotent progenitor cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;chromatin organization;transcription, DNA-templated;regulation of transcription, DNA-templated;transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;apoptotic process;cell cycle;chromosome segregation;signal transduction;glucocorticoid receptor signaling pathway;glucocorticoid mediated signaling pathway;positive regulation of transcription by RNA polymerase II;cell division;cellular response to steroid hormone stimulus;cellular response to glucocorticoid stimulus;cellular response to dexamethasone stimulus;cellular response to transforming growth factor beta stimulus
• Cellular component: nucleus;nucleoplasm;cytoplasm;mitochondrial matrix;microtubule organizing center;spindle;cytosol;nuclear speck;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;core promoter binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;RNA binding;nuclear receptor activity;glucocorticoid receptor activity;steroid binding;protein binding;zinc ion binding;protein kinase binding;SUMO binding;Hsp90 protein binding;steroid hormone binding