RARA

protein-coding

retinoic acid receptor alpha, the group of Retinoic acid receptors

Gene summary

This gene represents a nuclear retinoic acid receptor. The encoded protein, retinoic acid receptor alpha, regulates transcription in a ligand-dependent manner. This gene has been implicated in regulation of development, differentiation, apoptosis, granulopoeisis, and transcription of clock genes. Translocations between this locus and several other loci have been associated with acute promyelocytic leukemia. Alternatively spliced transcript variants have been found for this locus.[provided by RefSeq, Sep 2010]

MANE transcript

NM_000964.4

Inheritance

ClinVar variants

P:1U:48B:6

Top phenotype

Familial meningioma

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr17:40,309,180-40,357,643

External References & Databases

Ensembl (ENSG00000131759)

Transcript & Mutation Effects

hg38 • Region Span ~48.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

acute promyelocytic leukemiaNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0012883

Submitter: Ambry Genetics

craniosynostosisMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0015469

Submitter: PanelApp Australia

multiple congenital anomalies/dysmorphic syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0019042

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RARA variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 37

not providedTotal: 11

Familial meningiomaTotal: 3

Tretinoin responseTotal: 2

RARA-related conditionTotal: 2

Colorectal carcinomaTotal: 1

Mendelian syndromes with cleft lip/palateTotal: 1

Inborn genetic diseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000964.4. 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			2 clinvar	5 clinvar	1 clinvar	8
missense		1 clinvar	45 clinvar			46
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	48	5	1	55

Highest pathogenic variant AF is 6.8406285e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000964.4	RefSeq	NP_000955.1	8	MANE Select
ENST00000254066.10	Ensembl	ENSP00000254066.5	8	MANE Select
NM_001024809.4	RefSeq	NP_001019980.1	8	Standard
NM_001145301.3	RefSeq	NP_001138773.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rarab	Danio rerio	Structure: pectoral fin fold Quality: absent abnormal

Gene / Model

Organism

Observed Phenotype

rarab

Danio rerio

Structure: pectoral fin fold

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Acute myeloid leukemia - Homo sapiens (human)
Estrogen signaling pathway - Homo sapiens (human)
Th17 cell differentiation - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
ureteric bud development
neural tube closure
liver development
glandular epithelial cell development

Molecular Function

translation repressor activity, mRNA regulatory element binding
transcription regulatory region sequence-specific DNA binding
RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
retinoic acid binding

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000254066
Coding exons: 8
Length: 47651
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125742
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.08	144	292	0.493	0.0000184	2990
Missense (PolyPhen)		38	132.02	0.28783		1279
Synonymous	0.101	129	130	0.989	0.00000923	923
Loss of Function	3.62	2	19.1	0.105	0.00000103	219

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000038	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis. Has a role in the survival of early spermatocytes at the beginning prophase of meiosis. In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes. In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). {ECO:0000250|UniProtKB:P11416, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:20215566}.;
Disease: DISEASE: Note=Chromosomal aberrations involving RARA are commonly found in acute promyelocytic leukemia. Translocation t(11;17)(q32;q21) with ZBTB16/PLZF; translocation t(15;17)(q21;q21) with PML; translocation t(5;17)(q32;q11) with NPM. The PML-RARA oncoprotein requires both the PML ring structure and coiled-coil domain for both interaction with UBE2I, nuclear microspeckle location and sumoylation. In addition, the coiled- coil domain functions in blocking RA-mediated transactivation and cell differentiation. {ECO:0000269|PubMed:12691149, ECO:0000269|PubMed:8302850, ECO:0000269|PubMed:8562957}.;

Recessive Scores

pRec: 0.886

Intolerance Scores

LoFtool: 0.0723
RVIS EVS: -0.47
RVIS percentile EVS: 23.25

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.981

Gene Damage Prediction

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