NR2F1
protein-codingnuclear receptor subfamily 2 group F member 1, the group of Nuclear receptor subfamily 2 group F
Gene summary
The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator. The encoded protein acts as a homodimer and binds to 5'-AGGTCA-3' repeats. Defects in this gene are a cause of Bosch-Boonstra optic atrophy syndrome (BBOAS). [provided by RefSeq, Apr 2014]
- ERBAL3
- TFCOUP1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~11.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014320
Submitter: ClinGen
*NR2F1* was first reported in relation to autosomal dominant Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) in 2014 (PMID: 24462372). BBSOAS is characterized by visual impairment due to optic nerve abnormalities and/or cortical visual impairment, developmental delay, and intellectual disability. Additional findings may include hypotonia, seizures, autism spectrum disorder or autistic features, and hearing defects (PMIDs: 24462372, 26986877, 32275123). *NR2F1* variants, including missense, nonsense, frameshift and in-frame deletion variants, as well as large deletions, have been identified in over 50 individuals with BBSOAS (PMID: 32275123). Only 8 probands (PMIDs: 24462372, 26986877, 32275123) are included in this curation because the maximum score for genetic evidence has been reached. The disease mechanism is haploinsufficiency (PMIDs: 24462372, 26986877). However, a dominant-negative mechanism has been proposed for variants in the DNA binding domain (DBD) of the protein (PMIDs: 26986877, 32275123). Patients with variants in the DBD presented with more severe phenotypes, with increased prevalence of seizures and abnormal brain MRI findings compared to those with a deletion or coding variant outside of the DBD (PMIDs: 26986877, 32275123). This gene-disease relationship is also supported by experimental evidence, including a mouse model and in vitro expression studies (PMIDs: 31600777, 26986877). In summary, *NR2F1* is definitively associated with Bosch-Boonstra-Schaaf optic atrophy syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on February 16, 2022 (SOP Version 8).
Inheritance Pattern: AD
Disease ID:MONDO:0014320
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014320
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014320
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014320
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0014320
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Neurologic; Ophthalmologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NR2F1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005654.6. 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 | 6 | 123 | 1 | 130 | ||
| missense | 14 | 68 | 151 | 15 | 3 | 251 |
| nonsense | 17 | 10 | 1 | 28 | ||
| start loss | 4 | 1 | 5 | |||
| frameshift | 18 | 16 | 3 | 37 | ||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 1 | 3 | ||
| Total | 54 | 96 | 162 | 138 | 4 | 454 |
Highest pathogenic variant AF is 0.000024345964
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005645.1 | 3 | MANE Select | |
| Ensembl | ENSP00000325819.3 | 3 | MANE Select | |
| RefSeq | NP_001397683.1 | 3 | Standard | |
| Ensembl | ENSP00000514864.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nr2f1a | Danio rerio | Structure: axial blood vessel Quality: disrupted abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- NHR
- Nuclear Receptors
- Adipogenesis
- Gene expression (Transcription)
- mechanism of gene regulation by peroxisome proliferators via ppara
Biological Process
- negative regulation of transcription by RNA polymerase II
- transcription initiation from RNA polymerase II promoter
- signal transduction
- negative regulation of neuron projection development
- 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 factor activity
- steroid hormone receptor activity
Cellular Component
- nucleus
- nucleoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000327111
- Coding exons
- 3
- Length
- 11279
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.17 | 63 | 247 | 0.255 | 0.0000138 | 2735 |
| Missense (PolyPhen) | 18 | 102.52 | 0.17558 | 1048 | ||
| Synonymous | 0.632 | 105 | 114 | 0.925 | 0.00000681 | 874 |
| Loss of Function | 3.66 | 0 | 15.6 | 0.00 | 7.59e-7 | 154 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| 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 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Coup (chicken ovalbumin upstream promoter) transcription factor binds to the ovalbumin promoter and, in conjunction with another protein (S300-II) stimulates initiation of transcription. Binds to both direct repeats and palindromes of the 5'-AGGTCA-3' motif. Represses transcriptional activity of LHCG. {ECO:0000269|PubMed:10644740, ECO:0000269|PubMed:11682620}.;
- Disease
- DISEASE: Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS) [MIM:615722]: An autosomal dominant disorder characterized by optic atrophy associated with developmental delay and intellectual disability. Most patients also have evidence of cerebral visual impairment. {ECO:0000269|PubMed:24462372}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.113
Intolerance Scores
- RVIS EVS
- -0.34
- RVIS percentile EVS
- 30.07
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Low | Medium |