chrX-30304690-GA-G
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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
NM_000475.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.20
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 |
---|---|---|---|---|---|---|---|
NR0B1 | NM_000475.5 | c.1301del | p.Phe434SerfsTer3 | frameshift_variant | 2/2 | ENST00000378970.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR0B1 | ENST00000378970.5 | c.1301del | p.Phe434SerfsTer3 | frameshift_variant | 2/2 | 1 | NM_000475.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 24
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 submitter | clinical testing | GeneDx | May 20, 2016 | The 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
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at