rs111787313

Positions:

• chrX-38285780-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001034853.2(RPGR):​c.3219C>T​(p.Gly1073=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,205,849 control chromosomes in the GnomAD database, including 1,654 homozygotes. There are 16,653 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (286 hom., 2046 hem., cov: 21)
  • Exomes 𝑓: 0.038 (1368 hom. 14607 hem.)
• Consequence: RPGR NM_001034853.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.55

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-38285780-G-A is Benign according to our data. Variant chrX-38285780-G-A is described in ClinVar as [Benign]. Clinvar id is 403390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38285780-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.3219C>T	p.Gly1073=	synonymous_variant	15/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.3219C>T	p.Gly1073=	synonymous_variant	15/15		NM_001034853.2	ENSP00000495537	A2

Frequencies

GnomAD3 genomes AF: 0.0644 AC: 6956 AN: 107954 Hom.: 287 Cov.: 21 AF XY: 0.0663 AC XY: 2038 AN XY: 30734

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0250

Gnomad EAS AF: 0.0728

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0812

Gnomad MID AF: 0.0173

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0557

GnomAD3 exomes AF: 0.0800 AC: 14513 AN: 181522 Hom.: 822 AF XY: 0.0722 AC XY: 4844 AN XY: 67090

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.0697

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.0761

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0439

GnomAD4 exome AF: 0.0379 AC: 41559 AN: 1097849 Hom.: 1368 Cov.: 34 AF XY: 0.0402 AC XY: 14607 AN XY: 363293

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.203

Gnomad4 ASJ exome AF: 0.0192

Gnomad4 EAS exome AF: 0.0784

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.0697

Gnomad4 NFE exome AF: 0.0186

Gnomad4 OTH exome AF: 0.0406

GnomAD4 genome AF: 0.0645 AC: 6963 AN: 108000 Hom.: 286 Cov.: 21 AF XY: 0.0664 AC XY: 2046 AN XY: 30792

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0250

Gnomad4 EAS AF: 0.0731

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.0812

Gnomad4 NFE AF: 0.0202

Gnomad4 OTH AF: 0.0543

Alfa AF: 0.0337 Hom.: 331

Bravo AF: 0.0728

EpiCase AF: 0.0180

EpiControl AF: 0.0175

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 03, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.11
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5

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: rs111787313; hg19: chrX-38145033; COSMIC: COSV58835935;