NM_001034853.2:c.223A>G

Variant names:

• chrX-38322877-T-C
• rs111631988
• NM_001034853.2:c.223A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001034853.2(RPGR):​c.223A>G​(p.Ile75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,208,675 control chromosomes in the GnomAD database, including 224 homozygotes. There are 5,304 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.032 (85 hom., 1018 hem., cov: 23)
  • Exomes 𝑓: 0.012 (139 hom. 4286 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: 0.0920
• Publications: 6 publications found

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]

RPGR Gene-Disease associations (from GenCC):

• retinitis pigmentosa 3

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• RPGR-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• primary ciliary dyskinesia-retinitis pigmentosa syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macular degeneration, X-linked atrophic

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020298362).
• BP6: Variant X-38322877-T-C is Benign according to our data. Variant chrX-38322877-T-C is described in ClinVar as Benign. ClinVar VariationId is 100560.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.223A>G	p.Ile75Val	missense_variant	Exon 3 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.223A>G	p.Ile75Val	missense_variant	Exon 3 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-343244T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 3538 AN: 112158 Hom.: 84 Cov.: 23

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00148

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.00930

Gnomad OTH AF: 0.0217

GnomAD2 exomes AF: 0.0159 AC: 2909 AN: 183460 AF XY: 0.0147

Gnomad AFR exome AF: 0.0958

Gnomad AMR exome AF: 0.00769

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.00649

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0121 AC: 13283 AN: 1096466 Hom.: 139 Cov.: 28 AF XY: 0.0118 AC XY: 4286 AN XY: 362086

African (AFR) AF: 0.0903 AC: 2379 AN: 26357

American (AMR) AF: 0.00861 AC: 303 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 373 AN: 19356

East Asian (EAS) AF: 0.00252 AC: 76 AN: 30129

South Asian (SAS) AF: 0.0140 AC: 757 AN: 54108

European-Finnish (FIN) AF: 0.00222 AC: 90 AN: 40525

Middle Eastern (MID) AF: 0.0281 AC: 116 AN: 4128

European-Non Finnish (NFE) AF: 0.0101 AC: 8503 AN: 840627

Other (OTH) AF: 0.0149 AC: 686 AN: 46031

GnomAD4 genome AF: 0.0316 AC: 3548 AN: 112209 Hom.: 85 Cov.: 23 AF XY: 0.0296 AC XY: 1018 AN XY: 34373

African (AFR) AF: 0.0884 AC: 2729 AN: 30880

American (AMR) AF: 0.0164 AC: 174 AN: 10578

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 52 AN: 2653

East Asian (EAS) AF: 0.00445 AC: 16 AN: 3593

South Asian (SAS) AF: 0.0109 AC: 30 AN: 2750

European-Finnish (FIN) AF: 0.00148 AC: 9 AN: 6078

Middle Eastern (MID) AF: 0.0425 AC: 9 AN: 212

European-Non Finnish (NFE) AF: 0.00930 AC: 495 AN: 53242

Other (OTH) AF: 0.0221 AC: 34 AN: 1539

Alfa AF: 0.0126 Hom.: 542

Bravo AF: 0.0357

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00692 AC: 20

ESP6500AA AF: 0.0895 AC: 343

ESP6500EA AF: 0.00907 AC: 61

ExAC AF: 0.0168 AC: 2044

EpiCase AF: 0.0106

EpiControl AF: 0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:4 Other:1

-

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 22025579, 9399904, 27884173) -

not specified Benign:3

Jan 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ile75Val in exon 3 of RPGR: This variant is not expected to have clinical sign ificance because it has been identified in 8.9% (343/3833) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs111631988). -

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

X-linked cone-rod dystrophy 1;C1845667:Retinitis pigmentosa 3;C2749137:Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness;C3151784:Macular degeneration, X-linked atrophic Benign:1

Nov 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RPGR-related retinopathy Benign:1

Aug 04, 2025

ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001034853.2(RPGR):c.223A>G (p.Ile75Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 75. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01338 among hemizygous individuals, with 5304 variant alleles / 396,459 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.000005 (BA1). The computational predictor REVEL gives a score of 0.218, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. However, the splicing impact predictor SpliceAI gives a delta score of 0.12 for acceptor gain, which falls in the intermediate range above the ClinGen X-linked IRD VCEP recommended BP4 threshold of <0.1 but lower than the PP3 threshold of >0.2, so neither in silico code is met. In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0090
DANN	Benign	0.62
DEOGEN2	Benign	0.11	.;.;T;.;.;.;.;.
FATHMM_MKL	Benign	0.0049	N
LIST_S2	Benign	0.35	.;T;T;T;T;.;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.93	N;N;N;.;N;N;N;.
PhyloP100		0.092
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.51	N;.;N;.;.;.;N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;.;T;.;.;.;.;.
Sift4G	Benign	1.0	T;.;T;.;.;.;T;.
Polyphen		0.0	B;B;.;.;.;.;.;.
Vest4		0.048
MPC		0.60
ClinPred		0.0064	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.78
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111631988; hg19: chrX-38182130;