RORA

RAR related orphan receptor A, the group of RAR related orphan receptors

Basic information

Region (hg38): 15:60488284-61229302

Links

ENSG00000069667 ∙ NCBI:6095 ∙ OMIM:600825 ∙ HGNC:10258 ∙ Uniprot:P35398 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, autosomal dominant 40 (Strong), mode of inheritance: AD
• intellectual developmental disorder with or without epilepsy or cerebellar ataxia (Moderate), mode of inheritance: AD
• intellectual developmental disorder with or without epilepsy or cerebellar ataxia (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	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	Neurologic	29656859

ClinVar

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

• Intellectual developmental disorder with or without epilepsy or cerebellar ataxia (7 variants)
• not provided (5 variants)
• Inborn genetic diseases (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RORA 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				18	4	22
missense	1	3	65	6		75
nonsense	7	4	2			13
start loss			1			1
frameshift	4	2		1		7
inframe indel			1			1
splice donor/acceptor (+/-2bp)	1	2				3
splice region			2	1		3
non coding			5	3	1	9
Total	13	11	74	28	5

Variants in RORA

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

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

Position	Type	Phenotype	Significance	ClinVar
15-60497425-GACATTCTAGAAGTGCTTAGGTGATAACATTT-G			Uncertain significance (Jun 10, 2022)
15-60497456-T-A		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (May 31, 2022)
15-60497467-T-G		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (Oct 27, 2022)
15-60497478-G-C			Uncertain significance (Dec 15, 2023)
15-60497529-G-A			Pathogenic (May 16, 2024)
15-60497541-G-C			Uncertain significance (May 16, 2024)
15-60497580-G-A		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Conflicting classifications of pathogenicity (Apr 30, 2024)
15-60497599-G-T		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Benign (Nov 07, 2021)
15-60497599-G-G			Benign (Aug 18, 2018)
15-60499900-G-C		Inborn genetic diseases	Uncertain significance (May 29, 2024)
15-60499902-A-G			Uncertain significance (Dec 03, 2019)
15-60499904-T-A		RORA-related disorder	Likely benign (Jul 01, 2024)
15-60499914-C-T		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (Nov 06, 2023)
15-60499915-G-A			Pathogenic (Dec 22, 2023)
15-60499916-G-T		Inborn genetic diseases	Uncertain significance (May 21, 2024)
15-60499917-T-C			Uncertain significance (Aug 30, 2022)
15-60499934-G-T		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (Feb 11, 2020)
15-60499944-G-A		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Likely benign (Oct 25, 2021)
15-60499953-AT-A		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Likely pathogenic (Jul 17, 2023)
15-60499954-T-C		Inborn genetic diseases	Uncertain significance (Apr 15, 2024)
15-60499995-C-T		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Likely pathogenic (Mar 28, 2023)
15-60500962-CTGACATCAGTACAAATGCAGAAA-AT		Inborn genetic diseases	Pathogenic (Aug 12, 2022)
15-60501002-T-G		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (Feb 08, 2021)
15-60501043-A-G		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (Mar 28, 2019)
15-60502752-C-A		Intellectual developmental disorder with or without epilepsy or cerebellar ataxia	Uncertain significance (Aug 06, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RORA	protein_coding	protein_coding	ENST00000261523	12	741036

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.401	0.599	125738	0	3	125741	0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.58	187	316	0.592	0.0000173	3661
Missense in Polyphen		19	76.604	0.24803		896
Synonymous	0.302	112	116	0.964	0.00000695	1015
Loss of Function	4.30	8	35.8	0.224	0.00000205	383

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000464	0.0000462
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.0000331	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5'-AGGTCA-3' preceded by a short A-T-rich sequence. Key regulator of embryonic development, cellular differentiation, immunity, circadian rhythm as well as lipid, steroid, xenobiotics and glucose metabolism. Considered to have intrinsic transcriptional activity, have some natural ligands like oxysterols that act as agonists (25-hydroxycholesterol) or inverse agonists (7-oxygenated sterols), enhancing or repressing the transcriptional activity, respectively. Recruits distinct combinations of cofactors to target genes regulatory regions to modulate their transcriptional expression, depending on the tissue, time and promoter contexts. Regulates genes involved in photoreceptor development including OPN1SW, OPN1SM and ARR3 and skeletal muscle development with MYOD1. Required for proper cerebellum development, regulates SHH gene expression, among others, to induce granule cells proliferation as well as expression of genes involved in calcium- mediated signal transduction. Regulates the circadian expression of several clock genes, including CLOCK, ARNTL/BMAL1, NPAS2 and CRY1. Competes with NR1D1 for binding to their shared DNA response element on some clock genes such as ARNTL/BMAL1, CRY1 and NR1D1 itself, resulting in NR1D1-mediated repression or RORA-mediated activation of clock genes expression, leading to the circadian pattern of clock genes expression. Therefore influences the period length and stability of the clock. Regulates genes involved in lipid metabolism such as apolipoproteins APOA1, APOA5, APOC3 and PPARG. In liver, has specific and redundant functions with RORC as positive or negative modulator of expression of genes encoding phase I and phase II proteins involved in the metabolism of lipids, steroids and xenobiotics, such as CYP7B1 and SULT2A1. Induces a rhythmic expression of some of these genes. In addition, interplays functionally with NR1H2 and NR1H3 for the regulation of genes involved in cholesterol metabolism. Also involved in the regulation of hepatic glucose metabolism through the modulation of G6PC and PCK1. In adipose tissue, plays a role as negative regulator of adipocyte differentiation, probably acting through dual mechanisms. May suppress CEBPB-dependent adipogenesis through direct interaction and PPARG-dependent adipogenesis through competition for DNA-binding. Downstream of IL6 and TGFB and synergistically with RORC isoform 2, is implicated in the lineage specification of uncommitted CD4(+) T-helper (T(H)) cells into T(H)17 cells, antagonizing the T(H)1 program. Probably regulates IL17 and IL17F expression on T(H) by binding to the essential enhancer conserved non-coding sequence 2 (CNS2) in the IL17-IL17F locus. Involved in hypoxia signaling by interacting with and activating the transcriptional activity of HIF1A. May inhibit cell growth in response to cellular stress. May exert an anti- inflammatory role by inducing CHUK expression and inhibiting NF- kappa-B signaling. {ECO:0000269|PubMed:10478845, ECO:0000269|PubMed:11053433, ECO:0000269|PubMed:11252722, ECO:0000269|PubMed:11554739, ECO:0000269|PubMed:12467577, ECO:0000269|PubMed:14570920, ECO:0000269|PubMed:15781255, ECO:0000269|PubMed:15790933, ECO:0000269|PubMed:16462772, ECO:0000269|PubMed:17512500, ECO:0000269|PubMed:18005000, ECO:0000269|PubMed:18354202, ECO:0000269|PubMed:18658046, ECO:0000269|PubMed:19965867, ECO:0000269|PubMed:21499262, ECO:0000269|PubMed:7926749, ECO:0000269|PubMed:9328355, ECO:0000269|PubMed:9862959}.
• Pathway: Circadian rhythm - Homo sapiens (human);Inflammatory bowel disease (IBD) - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);NHR;Circadian Clock;Nuclear Receptors;White fat cell differentiation;Adipogenesis;BMAL1-CLOCK,NPAS2 activates circadian gene expression;Development and heterogeneity of the ILC family;Interleukin-4 and 13 signaling;White fat cell differentiation;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Gene expression (Transcription);Circadian Clock;Generic Transcription Pathway;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;RORA activates gene expression;HIF-1-alpha transcription factor network (Consensus)

Recessive Scores

• pRec: 0.178

Intolerance Scores

• loftool: 0.0171
• rvis_EVS: -0.96
• rvis_percentile_EVS: 9.09

Haploinsufficiency Scores

• pHI: 0.829
• hipred: Y
• hipred_score: 0.758
• ghis: 0.580

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.996

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Rora
• Phenotype: immune system 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); 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); 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; taste/olfaction phenotype; endocrine/exocrine gland phenotype; 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: angiogenesis;regulation of transcription, DNA-templated;transcription initiation from RNA polymerase II promoter;xenobiotic metabolic process;nitric oxide biosynthetic process;regulation of smoothened signaling pathway;positive regulation of vascular endothelial growth factor production;regulation of glucose metabolic process;regulation of steroid metabolic process;cytokine-mediated signaling pathway;cerebellar Purkinje cell differentiation;cerebellar granule cell precursor proliferation;intracellular receptor signaling pathway;circadian regulation of gene expression;cellular response to sterol;cholesterol homeostasis;muscle cell differentiation;positive regulation of circadian rhythm;regulation of macrophage activation;negative regulation of I-kappaB kinase/NF-kappaB signaling;steroid hormone mediated signaling pathway;negative regulation of fat cell differentiation;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;cGMP metabolic process;negative regulation of inflammatory response;regulation of transcription involved in cell fate commitment;triglyceride homeostasis;cellular response to interleukin-1;cellular response to tumor necrosis factor;cellular response to hypoxia;T-helper 17 cell differentiation
• Cellular component: nucleus;nucleoplasm
• Molecular function: RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;transcription corepressor binding;transcription coactivator binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;DNA-binding transcription factor activity;steroid hormone receptor activity;nuclear receptor activity;protein binding;beta-catenin binding;transcription factor binding;oxysterol binding;zinc ion binding;sequence-specific DNA binding;ligand-activated transcription factor activity