ESR1

protein-coding

estrogen receptor 1, the group of Estrogen receptors

Gene summary

This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

Previous symbols:

MANE transcript

NM_000125.4

Inheritance

ClinVar variants

P:4U:48B:35

Top phenotype

Estrogen resistance

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr6:151,656,691-152,129,619

External References & Databases

Ensembl (ENSG00000091831)

Transcript & Mutation Effects

hg38 • Region Span ~472.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

estrogen resistance syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014148

Submitter: Ambry Genetics

estrogen resistance syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014148

Submitter: PanelApp Australia

estrogen resistance syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014148

Submitter: Orphanet

estrogen resistance syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014148

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Estrogen resistanceAR

Manifestation: Endocrine

Intervention: General

Rationale: 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

Refs: 8090165; 8961262; 9396482; 18505767; 23841731

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ESR1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 56

not specifiedTotal: 30

ESR1-related disorderTotal: 10

Estrogen resistance syndromeTotal: 6

Familial cancer of breastTotal: 4

Migraine with or without aura, susceptibility to, 1Total: 2

Estrogen receptor mutant, temperature-sensitiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000125.4. 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	20 clinvar	4 clinvar	26
missense	2 clinvar	1 clinvar	45 clinvar	8 clinvar	3 clinvar	59
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	3	1	48	28	7	87

Highest pathogenic variant AF is 0.0000013687568

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000125.4	RefSeq	NP_000116.2	8	MANE Select
ENST00000206249.8	Ensembl	ENSP00000206249.3	8	MANE Select
NM_001122740.2	RefSeq	NP_001116212.1	8	Standard
NM_001122741.2	RefSeq	NP_001116213.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
esr1	Danio rerio	Structure: posterior lateral line primordium Quality: physical object quality abnormal

Gene / Model

Organism

Observed Phenotype

esr1

Danio rerio

Structure: posterior lateral line primordium

Quality: physical object quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Breast cancer - Homo sapiens (human)
Thyroid hormone signaling pathway - Homo sapiens (human)
Estrogen signaling pathway - Homo sapiens (human)
Endocrine and other factor-regulated calcium reabsorption - Homo sapiens (human)
Proteoglycans in cancer - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
antral ovarian follicle growth
epithelial cell development
chromatin remodeling
transcription, DNA-templated

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
TFIIB-class transcription factor binding
transcription coactivator binding
DNA-binding transcription activator activity, RNA polymerase II-specific

Cellular Component

nuclear chromatin
nucleus
nucleoplasm
cytoplasm
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000440973
Coding exons: 8
Length: 472929
Individuals with no LoFs: 125694
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125696
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.61	258	342	0.755	0.0000193	3869
Missense (PolyPhen)		39	119.13	0.32737		1394
Synonymous	-1.24	160	141	1.13	0.00000807	1176
Loss of Function	4.45	1	25.0	0.0400	0.00000141	277

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA- binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF- kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA- binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full-length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1. {ECO:0000269|PubMed:10681512, ECO:0000269|PubMed:10816575, ECO:0000269|PubMed:11477071, ECO:0000269|PubMed:11682626, ECO:0000269|PubMed:14764652, ECO:0000269|PubMed:15078875, ECO:0000269|PubMed:15891768, ECO:0000269|PubMed:16043358, ECO:0000269|PubMed:16617102, ECO:0000269|PubMed:16684779, ECO:0000269|PubMed:17922032, ECO:0000269|PubMed:17932106, ECO:0000269|PubMed:18247370, ECO:0000269|PubMed:19350539, ECO:0000269|PubMed:20074560, ECO:0000269|PubMed:20705611, ECO:0000269|PubMed:21330404, ECO:0000269|PubMed:22083956, ECO:0000269|PubMed:7651415, ECO:0000269|PubMed:9328340}.;
Disease: DISEASE: Estrogen resistance (ESTRR) [MIM:615363]: A disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present. {ECO:0000269|PubMed:23841731, ECO:0000269|PubMed:27754803}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.951

Intolerance Scores

LoFtool: 0.00317
RVIS EVS: 0.24
RVIS percentile EVS: 69.46

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