X-38285819-TTC-T
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_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
NM_001034853.2 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
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GnomAD3 exomes AF: 0.0000111 AC: 2AN: 180966Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 66938
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GnomAD4 exome AF: 0.00000182 AC: 2AN: 1097892Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 363340
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GnomAD4 genome Cov.: 20
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 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
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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