rs137852550

Positions:

• chrX-38317418-C-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Moderate

The NM_001034853.2(RPGR):​c.517G>C​(p.Gly173Arg) 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.81

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 12 ACMG points.

• PS1: Transcript NM_001034853.2 (RPGR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a repeat RCC1 3 (size 49) in uniprot entity RPGR_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) 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-38317418-C-G is Pathogenic according to our data. Variant chrX-38317418-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9916.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-38317418-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.517G>C	p.Gly173Arg	missense_variant	6/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.517G>C	p.Gly173Arg	missense_variant	6/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

RETINITIS PIGMENTOSA, SINORESPIRATORY INFECTIONS, AND DEAFNESS Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2003

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2016

- -

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	Uncertain	24
DANN	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H;H;.;H;H;H;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.7	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.70
MutPred		0.94		Loss of ubiquitination at K175 (P = 0.0508);Loss of ubiquitination at K175 (P = 0.0508);Loss of ubiquitination at K175 (P = 0.0508);Loss of ubiquitination at K175 (P = 0.0508);Loss of ubiquitination at K175 (P = 0.0508);Loss of ubiquitination at K175 (P = 0.0508);Loss of ubiquitination at K175 (P = 0.0508);.;Loss of ubiquitination at K175 (P = 0.0508);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs137852550; hg19: chrX-38176671;