X-38269735-A-C

Position:

• chrX-38269735-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000328.3(RPGR):​c.2339T>G​(p.Ile780Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPGR NM_000328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.361

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053961307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_000328.3	c.2339T>G	p.Ile780Ser	missense_variant	19/19		NP_000319.1
RPGR	NM_001367245.1	c.2336T>G	p.Ile779Ser	missense_variant	19/19		NP_001354174.1
RPGR	NM_001367246.1	c.2153T>G	p.Ile718Ser	missense_variant	18/18		NP_001354175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000339363.7	c.2954T>G	p.Ile985Ser	missense_variant	18/18	5		ENSP00000343671	P4
RPGR	ENST00000642395.2	c.2339T>G	p.Ile780Ser	missense_variant	19/19			ENSP00000493468	A2
RPGR	ENST00000644337.1	c.2153T>G	p.Ile718Ser	missense_variant	18/18			ENSP00000494557

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 11, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 780 of the RPGR protein (p.Ile780Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RPGR-related conditions. 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 not expected to disrupt RPGR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.3
DANN	Benign	0.41
DEOGEN2	Benign	0.030	.;.;T;.;.
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.50	.;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.054	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	0.83	N;.;N;.;.
REVEL	Benign	0.019
Sift	Benign	0.086	T;.;T;.;.
Sift4G	Benign	0.68	T;.;T;.;.
Polyphen		0.10	B;B;.;.;.
Vest4		0.13
MutPred		0.26		Loss of stability (P = 0.0275);Loss of stability (P = 0.0275);.;.;.;
MVP		0.043
ClinPred		0.049	T
GERP RS		-0.44
Varity_R		0.044

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-38128988;