NR0B1

Chr X

nuclear receptor subfamily 0 group B member 1

Also known as: AHC, AHCH, AHX, DAX-1, DAX1, DSS, GTD, HHG

NCBI Gene: 190 ENSG00000169297 UniProt: P51843

This gene encodes a nuclear receptor corepressor that inhibits transcriptional activity of other nuclear receptors and is essential for development of the hypothalamic-pituitary-adrenal-gonadal axis. Mutations cause X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism, as well as 46,XY sex reversal with dosage sensitivity. The gene shows X-linked recessive inheritance and is highly constrained against loss-of-function variants.

ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that contains a DNA-binding domain. The encoded protein acts as a dominant-negative regulator of transcription which is mediated by the retinoic acid receptor. This protein also functions as an anti-testis gene by acting antagonistically to Sry. Mutations in this gene result in both X-linked congenital adrenal hypoplasia and hypogonadotropic hypogonadism. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.28

Clinical Summary— NR0B1

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

33 unique Pathogenic / Likely Pathogenic· 91 VUS of 277 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.970

Z-score 3.06

OE 0.00 (0.00–0.28)

Highly constrained

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

Missense Constraint?

1.08Z-score

OE missense 0.78 (0.68–0.89)

150 obs / 192.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.28)

0≤0.351.4

Missense OE?0.78 (0.68–0.89)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 0 / 10.9Missense obs/exp: 150 / 192.2Syn Z: -0.84

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNR0B1-related adrenal hypoplasia, congenitalLOFXLR

This gene — mechanism propensity

0.2997th %ile

GOF

0.4283th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 85% of P/LP variants are LoF · LOEUF 0.28 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

277 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26

Likely Pathogenic7

VUS91

Likely Benign127

Benign16

Conflicting7

Pathogenic

Likely Pathogenic

VUS

127

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	24	0	2	0	26
Likely Pathogenic	4	3	0	0	7
VUS	2	88	1	0	91
Likely Benign	0	5	5	117	127
Benign	0	6	1	9	16
Conflicting	—				7
Total	30	102	9	126	274

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

23 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap NR0B1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →