rs62642057

Variant names:

• chrX-38304746-C-A
• NM_001034853.2:c.823G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-38304746-C-A
• chrX-38304746-C-G
• chrX-38304746-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001034853.2(RPGR):​c.823G>T​(p.Gly275Cys) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a repeat RCC1 5 (size 51) in uniprot entity RPGR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001034853.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant X-38304746-C-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.823G>T	p.Gly275Cys	missense_variant	Exon 8 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.823G>T	p.Gly275Cys	missense_variant	Exon 8 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-361375C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 275 of the RPGR protein (p.Gly275Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of retinitis pigmentosa (internal data). ClinVar contains an entry for this variant (Variation ID: 2118600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RPGR protein function with a positive predictive value of 95%. 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, 31456290). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.78
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;.;D;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.93	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;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-8.2	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		0.90
MutPred		0.96		Gain of catalytic residue at G275 (P = 0.0635);Gain of catalytic residue at G275 (P = 0.0635);Gain of catalytic residue at G275 (P = 0.0635);Gain of catalytic residue at G275 (P = 0.0635);Gain of catalytic residue at G275 (P = 0.0635);Gain of catalytic residue at G275 (P = 0.0635);Gain of catalytic residue at G275 (P = 0.0635);.;Gain of catalytic residue at G275 (P = 0.0635);
MVP		0.99
MPC		1.8
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)		0.020		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-38163999;