rs771214648

chrX-38285819-TTC-T

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.3178_3179del(p.Glu1060ArgfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,097,892 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: -0.129

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]

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. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38285819-TTC-T is Pathogenic according to our data. Variant chrX-38285819-TTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 216990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38285819-TTC-T is described in Lovd as [Pathogenic]. Variant chrX-38285819-TTC-T is described in Lovd as [Likely_pathogenic]. Variant chrX-38285819-TTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.3178_3179del	p.Glu1060ArgfsTer18	frameshift_variant	15/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.3178_3179del	p.Glu1060ArgfsTer18	frameshift_variant	15/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 180966 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66938

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097892 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 363340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 28, 2017	- -

Retinitis pigmentosa 3 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Blueprint Genetics

-

- -

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 30, 2023

This sequence change creates a premature translational stop signal (p.Glu1060Argfs*18) in the RPGR (ORF15) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 93 amino acid(s) of the RPGR (ORF15) protein. This variant is present in population databases (rs771214648, gnomAD 0.001%). This premature translational stop signal has been observed in individuals with retinitis pigmentosa (PMID: 16936086, 25097241). This variant is also known as ORF15+1422_1423delAG. ClinVar contains an entry for this variant (Variation ID: 216990). 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. For these reasons, this variant has been classified as Pathogenic. -

Cone-rod dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Feb 26, 2024

- -

Macular degeneration, X-linked atrophic Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Medical Molecular Genetics, University of Zurich

Dec 21, 2020

- -

X-linked cone-rod dystrophy 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

UCLA Clinical Genomics Center, UCLA

Oct 23, 2012

- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 31, 2018

- -

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

LitVar

Other links and lift over

dbSNP: rs771214648; hg19: chrX-38145072;