rs41312104

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.1598C>T(p.Thr533Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,207,527 control chromosomes in the GnomAD database, including 288 homozygotes. There are 8,907 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T533A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 38 hom., 621 hem., cov: 22)

Exomes 𝑓: 0.024 ( 250 hom. 8286 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10O:1

Conservation

PhyloP100: -0.0500

Publications

7 publications found

Variant links:

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

RPGR links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0017929971).

BP6

Variant X-38288016-G-A is Benign according to our data. Variant chrX-38288016-G-A is described in ClinVar as Benign. ClinVar VariationId is 92854.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0199 (2225/111643) while in subpopulation NFE AF = 0.029 (1540/53134). AF 95% confidence interval is 0.0278. There are 38 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 2225 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.1598C>T	p.Thr533Met	missense_variant	Exon 14 of 15	ENST00000645032.1	NP_001030025.1	Q92834-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 link	c.1598C>T	p.Thr533Met	missense_variant	Exon 14 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-378105G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

2225

AN:

111591

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0439

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00150

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0420

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0189

AC:

3446

AN:

182733

AF XY:

0.0182

show subpopulations

Gnomad AFR exome

AF:

0.00411

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0439

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0238

AC:

26108

AN:

1095884

Hom.:

250

Cov.:

AF XY:

0.0229

AC XY:

8286

AN XY:

362224

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00379

AC:

100

AN:

26368

American (AMR)

AF:

0.0132

AC:

465

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.0410

AC:

794

AN:

19349

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30194

South Asian (SAS)

AF:

0.00346

AC:

187

AN:

54108

European-Finnish (FIN)

AF:

0.0214

AC:

864

AN:

40422

Middle Eastern (MID)

AF:

0.0396

AC:

163

AN:

4120

European-Non Finnish (NFE)

AF:

0.0268

AC:

22482

AN:

840105

Other (OTH)

AF:

0.0229

AC:

1052

AN:

46028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.399

Heterozygous variant carriers

835

1670

2504

3339

4174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

824

1648

2472

3296

4120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0199

AC:

2225

AN:

111643

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

621

AN XY:

33895

show subpopulations

African (AFR)

AF:

0.00364

AC:

112

AN:

30783

American (AMR)

AF:

0.0160

AC:

168

AN:

10497

Ashkenazi Jewish (ASJ)

AF:

0.0439

AC:

116

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00150

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.0192

AC:

114

AN:

5927

Middle Eastern (MID)

AF:

0.0413

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0290

AC:

1540

AN:

53134

Other (OTH)

AF:

0.0151

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0263

Hom.:

1230

Bravo

AF:

0.0190

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0322

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.0293

AC:

197

ExAC

AF:

0.0195

AC:

2362

EpiCase

AF:

0.0281

EpiControl

AF:

0.0287

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

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.Thr533Met in exon 14 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (197/6728) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41312104). -

Oct 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 11, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Jul 18, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 26, 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. -

RPGR-related retinopathy

Benign:1

Aug 03, 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.1598C>T (p.Thr533Met) is a missense variant predicted to cause substitution of threonine by methionine at amino acid 533. This variant is present in gnomAD v.4.1.0 at a frequency of 0.02249 among hemizygous individuals, with 8,907 variant alleles / 396,119 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been observed in more than 6 individuals with no features or family history of RPGR-related RP, a condition with full penetrance at an early age (PMIDs: 10482958, 11992260, 10980543, 19377476). However, it is not clear whether these individuals underwent a complete visual examination, so BS2 was not met. The computational predictor REVEL gives a score of 0.015, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.03, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_Strong). 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 and BP4_Strong. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.015

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.021

.;.;T;.;.;.

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.48

.;T;T;T;.;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.79

N;N;N;.;N;N

PhyloP100

-0.050

PrimateAI

Benign

0.34

PROVEAN

Benign

1.1

N;.;N;.;.;N

REVEL

Benign

0.015

Sift

Benign

0.16

T;.;T;.;.;.

Sift4G

Benign

0.14

T;.;T;.;.;T

Polyphen

0.27

B;B;.;.;.;.

Vest4

0.061

MPC

0.022

ClinPred

0.0098

GERP RS

-3.7

Varity_R

0.012

gMVP

0.061

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over