X-38285901-TCC-TC

Variant names:

• chrX-38285901-TC-T
• NM_001034853.2:c.3097delG

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001034853.2(RPGR):​c.3097delG​(p.Glu1033LysfsTer56) variant causes a frameshift 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 17)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.15

Genes affected

RPGR (HGNC:10295): (retinitis pigmentosa GTPase regulator) This gene encodes a protein with a series of six RCC1-like domains (RLDs), characteristic of the highly conserved guanine nucleotide exchange factors. The encoded protein is found in the Golgi body and interacts with RPGRIP1. This protein localizes to the outer segment of rod photoreceptors and is essential for their viability. Mutations in this gene have been associated with X-linked retinitis pigmentosa (XLRP). Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but the full-length natures of only some have been determined. [provided by RefSeq, Dec 2008]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 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. Fraction of 0.105 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38285901-TC-T is Pathogenic according to our data. Variant chrX-38285901-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 2138529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38285901-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.3097delG	p.Glu1033LysfsTer56	frameshift_variant	Exon 15 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.3097delG	p.Glu1033LysfsTer56	frameshift_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-380215delC		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 3 Pathogenic:1

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss-of-function is a known mechanism of disease for this gene. Gain-of-function has also been suggested as a mechanism for truncating variants in ORF15 (PMID: 14691151; PMID: 27995965). (N) 0109 - This gene is known to be associated with X-linked recessive disease. This gene is predominantly associated with X-linked recessive disease, however dominant inheritance patterns have also been reported for some variants (OMIM, PMID: 23372056). X-inactivation was associated with variable severity in females (PMID: 31953110). (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 15 of 15). Exon 15 is also known as ORF15 in the NM_001034853.1 transcript (PMID: 30193314). (P) 0253 - Variant is hemizygous. (N) 0301 - Variant is absent from gnomAD. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants located dowsntream and predicted to cause a truncated protein have been reported as pathogenic in individuals with retinal dystrophy (ClinVar; PMID: 23681342; 23372056, 27620828). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in patients with retinitis pigmentosa (PMID: 17195164; 10932196). (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Primary ciliary dyskinesia Pathogenic:1

Mar 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu1033Lysfs*56) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the RPGR (ORF15) protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RPGR (ORF15) protein in which other variant(s) (p.Leu1130Lysfs*13) have been determined to be pathogenic (PMID: 22264887; Invitae). 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 variant is also known as g.ORF15+1344delG. This premature translational stop signal has been observed in individual(s) with retinitis pigmentosa (PMID: 10932196). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-38145154;