chrX-30304699-AC-A
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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.1292del(p.Ser431IlefsTer6) 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: 23)
Consequence
NR0B1
NM_000475.5 frameshift
NM_000475.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.70
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-30304699-AC-A is Pathogenic according to our data. Variant chrX-30304699-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 2138497.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-30304699-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NR0B1 | NM_000475.5 | c.1292del | p.Ser431IlefsTer6 | frameshift_variant | 2/2 | ENST00000378970.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NR0B1 | ENST00000378970.5 | c.1292del | p.Ser431IlefsTer6 | frameshift_variant | 2/2 | 1 | NM_000475.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital adrenal hypoplasia, X-linked;C1848296:46,XY sex reversal 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 22, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NR0B1 protein in which other variant(s) (p.Ile439Glnfs*5) have been observed in individuals with NR0B1-related conditions (PMID: 22761912). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individuals with X-linked adrenal hypoplasia (PMID: 7609262, 26500747). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser431Ilefs*6) in the NR0B1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 40 amino acid(s) of the NR0B1 protein. - |
Computational scores
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Calibrated prediction
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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
Publications
No publications associated with this variant yet.