rs62642057

chrX-38304746-C-GchrX-38304746-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001034853.2(RPGR):c.823G>C(p.Gly275Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G275C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.74

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 18 ACMG points.

• PM1: In a repeat RCC1 5 (size 51) in uniprot entity RPGR_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_001034853.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38304746-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2118600.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-38304746-C-G is Pathogenic according to our data. Variant chrX-38304746-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 866638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.823G>C	p.Gly275Arg	missense_variant	8/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.823G>C	p.Gly275Arg	missense_variant	8/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 11, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly275 amino acid residue in RPGR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8817343, 16969763, 17724181, 23213406, 30622176, 31456290). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGR protein function. ClinVar contains an entry for this variant (Variation ID: 866638). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 32702353; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 275 of the RPGR protein (p.Gly275Arg). -

Retinal dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.9	H;H;H;.;H;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.3	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.89
MutPred		0.97		Loss of catalytic residue at L280 (P = 0.1215);Loss of catalytic residue at L280 (P = 0.1215);Loss of catalytic residue at L280 (P = 0.1215);Loss of catalytic residue at L280 (P = 0.1215);Loss of catalytic residue at L280 (P = 0.1215);Loss of catalytic residue at L280 (P = 0.1215);Loss of catalytic residue at L280 (P = 0.1215);.;Loss of catalytic residue at L280 (P = 0.1215);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.99

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: rs62642057; hg19: chrX-38163999;