X-30304581-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_000475.5(NR0B1):c.1411T>C(p.Ter471GlnextTer18) variant causes a stop lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NR0B1 NM_000475.5 stop_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.42

Genes affected

NR0B1 (HGNC:7960): (nuclear receptor subfamily 0 group B member 1) 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-30304581-A-G is Pathogenic according to our data. Variant chrX-30304581-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978419.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.287225).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR0B1	NM_000475.5	c.1411T>C	p.Ter471GlnextTer18	stop_lost	2/2	ENST00000378970.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR0B1	ENST00000378970.5	c.1411T>C	p.Ter471GlnextTer18	stop_lost	2/2	1	NM_000475.5	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital adrenal hypoplasia, X-linked Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Department of Endocrinology, Metabolism and Genetics, Henan Children's Hospital, Children's Hospital Affiliated to Zhengzhou University

Sep 27, 2016

The novel DAX1 stop-loss variant: c.1411T>C preceded the rare prolonged precocious puberty and primary adrenal insufficiency symptoms in the adrenal hypoplasia congenital boy. The precocious puberty symptoms recorded since at the boy's age of 5.9 yrs lasted till 15.1 yrs of age. This clinical inference contradicts the earlier case studies J.H.D. Bassett et al., 1999 and Okuhara et al., 2008 in which the adrenal hypoplasia congenital boys developed precocious puberty between 17 years to 18 years of age. Moreover, at 15.1 yrs of age: the boy showed the male stereotype characteristics of an adult-hood with the increased serum concentrations of total testosterone; luteinising hormones; follicle-stimulating hormones; adrenocorticotropic hormones; and the hyper-activation of the hypothalamic-pituitary-gonadal/adrenal axis diagnosed at the pre-pubertal stage. The stop-loss variant: c.1411T>C/p.X471Q by adding extra 18 amino acids at the C terminal domain of each chain A and chain B monomers of DAX1 homodimer is more likely to disturb the homodimer orientation. Indeed, this could effectively hinder the DAX1 functional interaction with the steroidogenic factor 1 (SF1) protein crucial in regulating the hypothalamic-pituitary-gonadal/adrenal axis responses via neuronal nitric oxide synthetase activation. This mechanistic hindrance paved by the disturbed DAX1-SF1 protein interactions could precede the prolonged precocious puberty in the adrenal hypoplasia congenital boy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	13
Dann	Benign	0.78
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	N
Vest4		0.073
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1926485824; hg19: chrX-30322698;