NR2F1

Chr 5AD

nuclear receptor subfamily 2 group F member 1

NCBI Gene: 7025 ENSG00000175745 UniProt: P10589 OMIM: 132890

This gene encodes a nuclear hormone receptor that functions as a transcriptional regulator, binding to specific DNA sequences to control gene expression. Mutations cause Bosch-Boonstra-Schaaf optic atrophy syndrome, which involves visual impairment and developmental delays with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.99, LOEUF 0.19), indicating that heterozygous loss is typically not tolerated in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— NR2F1

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Gene-Disease Validity (ClinGen)

Bosch-Boonstra-Schaaf optic atrophy syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.19LOEUF

pLI 0.995

Z-score 3.66

OE 0.00 (0.00–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

4.17Z-score

OE missense 0.25 (0.21–0.31)

63 obs / 247.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.19)

0≤0.351.4

Missense OE?0.25 (0.21–0.31)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 0 / 15.6Missense obs/exp: 63 / 247.3Syn Z: 0.63

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNR2F1-related Bosch-Boonstra-Schaaf optic atrophy syndromeLOFAD

This gene — mechanism propensity

0.2698th %ile

GOF

0.2497th %ile

LOF

0.88top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.19 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNNovel dominant-negative NR2F1 frameshift mutation and a phenotypic expansion of the Bosch-Boonstra-Schaaf optic atrophy syndrome.1

LOFOur findings indicate that NR2F1 has an important role in the development of the visual system and that haploinsuffiency can lead to optic atrophy with intellectual impairment.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References