X-38269721-T-C

Position:

• chrX-38269721-T-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.2353A>G​(p.Asn785Asp) 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: 22)
• Consequence: RPGR NM_000328.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.972

Genes affected

ENSG00000250349 (HGNC:):

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=0.06591365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_000328.3	c.2353A>G	p.Asn785Asp	missense_variant	19/19		NP_000319.1
RPGR	NM_001367245.1	c.2350A>G	p.Asn784Asp	missense_variant	19/19		NP_001354174.1
RPGR	NM_001367246.1	c.2167A>G	p.Asn723Asp	missense_variant	18/18		NP_001354175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-396400T>C		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

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

Ambry Genetics

May 30, 2024

The c.2353A>G (p.N785D) alteration is located in exon 19 (coding exon 19) of the RPGR gene. This alteration results from a A to G substitution at nucleotide position 2353, causing the asparagine (N) at amino acid position 785 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.94
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.030	.;.;T;.;.
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.40	.;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;N;.;.
PROVEAN	Benign	-0.70	N;.;N;.;.
REVEL	Benign	0.050
Sift	Benign	0.30	T;.;D;.;.
Sift4G	Benign	0.45	T;.;T;.;.
Polyphen		0.12	B;B;.;.;.
Vest4		0.062
MutPred		0.15		Loss of methylation at K782 (P = 0.0688);Loss of methylation at K782 (P = 0.0688);.;.;.;
MVP		0.19
ClinPred		0.081	T
GERP RS		2.3
Varity_R		0.13

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: rs1481491439; hg19: chrX-38128974;