• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
NR2F1 (HGNC:7975) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
nuclear receptor subfamily 2 group F member 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
ERBAL3, TFCOUP1
Alias symbols
EAR-3, COUP-TFI, TCFCOUP1, SVP44, COUPTF1
%HI
2.69(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.99(Read more about gnomAD pLI score)
LOEUF
0.19(Read more about gnomAD LOEUF score)
Cytoband
5q15
Genomic Coordinates
GRCh37/hg19: chr5:92918928-92930317 NCBI Ensembl UCSC
GRCh38/hg38: chr5:93583222-93594611 NCBI Ensembl UCSC
MANE Select Transcript
NM_005654.6 ENST00000327111.8 (Read more about MANE Select)
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}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-31161
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
08/09/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Bosch-Boonstra-Schaaf optic atrophy syndrome Monarch
HI Evidence:
  • PUBMED: 32275123
    Rech et al. (2020) identified 27 individuals with Bosch–Boonstra–Schaaf Optic Atrophy Syndrome (BBSOAS) from a Baylor College of Medicine cohort that previously had an NR2F1 variant identified through CMA, WES, or genome sequencing. These 27 individuals were then combined with 27 previously published individuals for a combined total of 54 participants presented. These individuals had a clinical diagnoses of developmental delay, speech delay, vision impairment, and hypotonia. Two participants have de novo indels, 3 participants have de novo multi-gene deletions, 4 participants have inherited deletions, and 3 participants have de novo nonsense variants. The rest of the participant population have missense variants, or a variant with unknown inheritance. No assays were performed to confirm a loss of function as the mechanism for the participants with missense variants identified.
  • PUBMED: 23300014
    Al-Kateb et al. (2013) used Genome-wide SNP analysis on a child with developmental delay, dysmorphic features, and bilateral optic atrophy associated with visual motor integration deficit and visual perceptual disorder. The participant was found to have a de novo 582 kb deletion including the genes FLJ42709, NR2F1, FAM172A, POU5F2, and MIR2277. The authors compared their patient's phenotype and genotype with other cited literature (Brown et al. (2009), Cardoso et al. (2009)) and found the overlapping segment within all of these individuals included FLJ42709 and NR2F1. FLJ42709 is an uncharacterized non-coding RNA.
  • PUBMED: 32712214
    Walsh et al. (2020) used trio exome sequencing on 4813 genes associated with known clinical features on an individual with developmental delay, autism spectrum disorder, seizures, hyperopia with severe reduction of vision, conductive hearing loss, and macrocephaly. The authors identified a de novo heterozygous deletion in NR2F1.
  • PUBMED: 24462372
    Bosch et al. (2014) report six individuals with variants involving NR2F1 and similar phenotypes, including 4 with de novo missense variants, 1 with a de novo deletion, and one with a deletion of unknown inheritance. Both of these deletions encompassed NR2F1 as well as other genes. The authors proposed that haploinsufficiency was the mechanism by which NR2F1 was contributing to this phenotype in these cases: Using a luciferase reporter assay, they showed that the 4 missense variants lost their ability to fully activate the NR2F1-COUP-TFI reporter, suggesting that these variants resulted in loss of function of the NR2F1-COUP-TFI product. Additionally, the group reported that the probability of identifying even 3 de novo variants in NR2F1 in a cohort of 56 individuals with CVI is p=1.40 x 10E-10, indicating that these observations were highly unlikely to occur by chance.
  • PUBMED: 34837429
    Billiet et al. (2021) describe the construction of the first NR2F1 locus‐specific database (LSDB), listing all patients and genetic variants referenced in the literature and unpublished cases from their laboratory. They report on 112 variants and 84 patients with BBSOAS. They summarize the most frequently observed pathogenic effects on the NR2F1 protein: 61% are missense variants, 14% are nonsense and 12% are frameshift variants leading to a premature protein truncation (ie a quarter of the variations would result in truncated proteins or their absence due to the nonsense‐mediated mRNA decay surveillance pathway). 10% lead to haploinsufficiency, either due to the complete deletion of the whole gene or as a consequence of a variant in the translation initiation codon on one allele. Two variants were a deletion of a single amnio acid. In most cases the variants were de novo but some rare familial cases were reported. They expand on the clinical spectrum stating that it ‘is heterogeneous, as some patients do not suffer from visual impairment and others display no neurodevelopmental delay’ and they note additional signs of hypotonia and feeding difficulties should be included in the spectrum.
HI Evidence Comments:
Bosch-Boonstra-Schaaf optic atrophy syndrome is characterized by visual impairment, developmental delay, and intellectual disability. Though most reported variants are missense (61% as described in Billiet et al. 2021), loss of function variants in NR2F1, including whole gene deletions, have been reported in affected individuals. Per Rech et al. 2020, evidence has been demonstrated to support both haploinsufficiency and dominant-negative as plausible mechanisms for disease: "...given that NR2F1 binds to DNA as a homodimer, that [variants in the DNA-binding domain, or DBD] reduce luciferase activity (indicative of transcriptional activity) beyond that of even a negative control, and that DBD variants have been associated with more severe phenotypes, a dominant-negative effect has been proposed (Chen et al., 2016, PMID: 26986877). The more severe phenotype may also be due to impaired binding of homodimerized NR2F1 to crucial NR2F1 targets when a missense variant in the DBD is present. In contrast, luciferase reporter assay data has shown that missense variants in the [ligand-binding domain, or LBD] and other regions outside of the DBD diminish but do not completely abolish transcriptional activity; these hypomorphic variants have previously been associated with comparatively mild observed clinical features (Chen et al., 2016). Haploinsufficiency due to nonsense and frameshift variants as well as whole-gene deletions of NR2F1 have also been associated with more mild features (Chen et al., 2016). Additionally, among patients with translation initiation variants, although the third codon of NR2F1 (ATG) could potentially serve as an alternative start codon, fibroblast data showed decreased NR2F1 protein levels (by 60%) and NR2F1 mRNA levels (by 45%); these findings suggest alterations in both translation and transcription and support a mechanism of haploinsufficiency for these variants leading to a milder phenotype (Chen et al., 2016)."

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)