rs62638637

Positions:

• chrX-38321041-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_001034853.2(RPGR):​c.296C>A​(p.Thr99Asn) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T99I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.55

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_001034853.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant X-38321041-G-T is Pathogenic according to our data. Variant chrX-38321041-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 9906.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-38321041-G-T is described in Lovd as [Pathogenic]. Variant chrX-38321041-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.296C>A	p.Thr99Asn	missense_variant	4/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.296C>A	p.Thr99Asn	missense_variant	4/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinitis pigmentosa 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;.;D;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.0	M;M;M;.;M;M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.2	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.84
MutPred		0.70		Gain of catalytic residue at T99 (P = 0.0601);Gain of catalytic residue at T99 (P = 0.0601);Gain of catalytic residue at T99 (P = 0.0601);Gain of catalytic residue at T99 (P = 0.0601);Gain of catalytic residue at T99 (P = 0.0601);Gain of catalytic residue at T99 (P = 0.0601);Gain of catalytic residue at T99 (P = 0.0601);.;Gain of catalytic residue at T99 (P = 0.0601);
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs62638637; hg19: chrX-38180294;