rs1555972943

Positions:

• chrX-30308175-GCCTAAGGCCAGTACCCTTAC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000378970.5(NR0B1):​c.1168+1_1168+20del variant causes a splice donor, splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NR0B1 ENST00000378970.5 splice_donor, splice_donor_5th_base, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.08

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-30308175-GCCTAAGGCCAGTACCCTTAC-G is Pathogenic according to our data. Variant chrX-30308175-GCCTAAGGCCAGTACCCTTAC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR0B1	NM_000475.5	c.1168+1_1168+20del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		ENST00000378970.5	NP_000466.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR0B1	ENST00000378970.5	c.1168+1_1168+20del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		1	NM_000475.5	ENSP00000368253	P1
NR0B1	ENST00000378963.1	c.283+1_283+20del		splice_donor_variant, splice_donor_5th_base_variant, intron_variant		2		ENSP00000368246

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital adrenal hypoplasia, X-linked Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Oct 27, 2017

- -

Congenital adrenal hypoplasia, X-linked;C1848296:46,XY sex reversal 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 1 of the NR0B1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant has not been reported in the literature in individuals affected with NR0B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 492857). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the C-terminus of the NR0B1 protein. Other variant(s) that disrupt this region (p.Gln395*, p.Asp459Glyfs*3, p.Ser431Ilefs*6) have been observed in individuals with NR0B1-related conditions (PMID: 7609262, 8855822). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555972943; hg19: chrX-30326292;