ESRRA

protein-coding

estrogen related receptor alpha, the group of Estrogen related receptors

Gene summary

The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1. [provided by RefSeq, Jun 2019]

Previous symbols:

ESRL1

MANE transcript

NM_004451.5

Inheritance

—

ClinVar variants

U:52B:4

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr11:64,305,497-64,316,743

External References & Databases

Ensembl (ENSG00000173153)

Transcript & Mutation Effects

hg38 • Region Span ~11.2 kb

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GenCC 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 ESRRA variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 49

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004451.5. 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 clinvar	2 clinvar	1 clinvar	4
missense			50 clinvar		1 clinvar	51
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	52	2	2	56

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 84 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004451.5	RefSeq	NP_004442.3	6	MANE Select
ENST00000000442.11	Ensembl	ENSP00000000442.6	6	MANE Select
NM_001282450.2	RefSeq	NP_001269379.1	6	Standard
NM_001282451.2	RefSeq	NP_001269380.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
esrra	Danio rerio	Structure: pharyngeal arch 3-7 Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

esrra

Danio rerio

Structure: pharyngeal arch 3-7

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NHR
Energy Metabolism
Nuclear Receptors
Mitochondrial biogenesis
Preimplantation Embryo

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription, DNA-templated
transcription initiation from RNA polymerase II promoter
mitochondrion organization
intracellular receptor signaling pathway

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA binding

Cellular Component

fibrillar center
nucleus
nucleoplasm
cytoplasm
microtubule cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000405666
Coding exons: 6
Length: 11172
Individuals with no LoFs: 124766
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 124772
p: 0.0000240

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.08	161	254	0.634	0.0000162	2616
Missense (PolyPhen)		26	89.12	0.29174		978
Synonymous	0.328	110	114	0.961	0.00000709	954
Loss of Function	2.99	3	15.8	0.189	9.23e-7	183

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00019	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000095	0.0000088	rare
South Asian	0.000068	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds to an ERR-alpha response element (ERRE) containing a single consensus half-site, 5'-TNAAGGTCA-3'. Can bind to the medium-chain acyl coenzyme A dehydrogenase (MCAD) response element NRRE-1 and may act as an important regulator of MCAD promoter. Binds to the C1 region of the lactoferrin gene promoter. Requires dimerization and the coactivator, PGC-1A, for full activity. The ERRalpha/PGC1alpha complex is a regulator of energy metabolism. Induces the expression of PERM1 in the skeletal muscle. {ECO:0000269|PubMed:12522104, ECO:0000269|PubMed:16150865, ECO:0000269|PubMed:17676930, ECO:0000269|PubMed:18063693, ECO:0000269|PubMed:23836911, ECO:0000269|PubMed:9271417}.;

Recessive Scores

pRec: 0.373

Intolerance Scores

RVIS EVS: -0.36
RVIS percentile EVS: 28.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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