chrX-30304690-GA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_000475.5(NR0B1):​c.1301del​(p.Phe434SerfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 24)

Consequence

NR0B1
NM_000475.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.20
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-30304690-GA-G is Pathogenic according to our data. Variant chrX-30304690-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 279854.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-30304690-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NR0B1NM_000475.5 linkuse as main transcriptc.1301del p.Phe434SerfsTer3 frameshift_variant 2/2 ENST00000378970.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NR0B1ENST00000378970.5 linkuse as main transcriptc.1301del p.Phe434SerfsTer3 frameshift_variant 2/21 NM_000475.5 P1P51843-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxMay 20, 2016The c.1301delT pathogenic variant in the NROB1 gene has been reported previously in a male with primary adrenal insufficiency (Argente et al., 2003). The c.1301delT variant causes a frameshift starting with codon Phenylalanine 434, changes this amino acid to a Serine residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Phe434SerfsX3. This variant is predicted to cause loss of normal protein function through protein truncation. The c.1301delT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1301delT as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886041215; hg19: chrX-30322807; API