rs5917557

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4BA1BS2

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.2341G>A (p.Ala781Thr) is a missense variant encoding the substitution of alanine with threonine at amino acid 781. This variant is present in gnomAD v.4.1.0 at a frequency of 0.1538 among hemizygous individuals, with 54,741 variant alleles / 356,024 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been identified in 13 healthy individuals meeting the BS2 requirement of no electroretinogram defects by the age of 30 years (PMIDs: 12657579, 18552978, 18552978, 32679846, BS2). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). 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, BS2, and BP4_moderate. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385291/MONDO:0100437/106

Frequency

Genomes: 𝑓 0.13 ( 785 hom., 1169 hem., cov: 11)

Exomes 𝑓: 0.16 ( 10122 hom. 53572 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.308

Publications

10 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 -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.2341G>A	p.Ala781Thr	missense_variant	Exon 15 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.2341G>A	p.Ala781Thr	missense_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-379463C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

10242

AN:

79301

Hom.:

784

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0817

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.214

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.0992

Gnomad MID

AF:

0.174

Gnomad NFE

AF:

0.166

Gnomad OTH

AF:

0.146

GnomAD2 exomes

AF:

0.122

AC:

13768

AN:

113184

AF XY:

0.119

show subpopulations

Gnomad AFR exome

AF:

0.0862

Gnomad AMR exome

AF:

0.0876

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.123

Gnomad NFE exome

AF:

0.173

Gnomad OTH exome

AF:

0.170

GnomAD4 exome

AF:

0.160

AC:

168047

AN:

1052147

Hom.:

10122

Cov.:

AF XY:

0.156

AC XY:

53572

AN XY:

344163

show subpopulations

African (AFR)

AF:

0.0877

AC:

2179

AN:

24855

American (AMR)

AF:

0.0916

AC:

2557

AN:

27902

Ashkenazi Jewish (ASJ)

AF:

0.233

AC:

4345

AN:

18629

East Asian (EAS)

AF:

0.000258

AC:

AN:

27117

South Asian (SAS)

AF:

0.0439

AC:

2185

AN:

49800

European-Finnish (FIN)

AF:

0.123

AC:

4604

AN:

37547

Middle Eastern (MID)

AF:

0.217

AC:

639

AN:

2947

European-Non Finnish (NFE)

AF:

0.176

AC:

144559

AN:

819095

Other (OTH)

AF:

0.158

AC:

6972

AN:

44255

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

5069

10138

15208

20277

25346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5264

10528

15792

21056

26320

<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:

0.129

AC:

10238

AN:

79331

Hom.:

785

Cov.:

AF XY:

0.0986

AC XY:

1169

AN XY:

11861

show subpopulations

African (AFR)

AF:

0.0815

AC:

1661

AN:

20375

American (AMR)

AF:

0.102

AC:

698

AN:

6816

Ashkenazi Jewish (ASJ)

AF:

0.214

AC:

436

AN:

2040

East Asian (EAS)

AF:

0.000386

AC:

AN:

2592

South Asian (SAS)

AF:

0.0272

AC:

AN:

1325

European-Finnish (FIN)

AF:

0.0992

AC:

360

AN:

3630

Middle Eastern (MID)

AF:

0.174

AC:

AN:

144

European-Non Finnish (NFE)

AF:

0.166

AC:

6796

AN:

40867

Other (OTH)

AF:

0.144

AC:

153

AN:

1064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

337

674

1011

1348

1685

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

204

306

408

510

<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:

0.164

Hom.:

10139

Bravo

AF:

0.135

TwinsUK

AF:

0.174

AC:

646

ALSPAC

AF:

0.173

AC:

501

ESP6500AA

AF:

0.0842

AC:

280

ESP6500EA

AF:

0.169

AC:

973

ExAC

AF:

0.0834

AC:

3127

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Jan 29, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

May 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Primary ciliary dyskinesia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

RPGR-related retinopathy

Benign:1

May 20, 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.2341G>A (p.Ala781Thr) is a missense variant encoding the substitution of alanine with threonine at amino acid 781. This variant is present in gnomAD v.4.1.0 at a frequency of 0.1538 among hemizygous individuals, with 54,741 variant alleles / 356,024 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been identified in 13 healthy individuals meeting the BS2 requirement of no electroretinogram defects by the age of 30 years (PMIDs: 12657579, 18552978, 18552978, 32679846, BS2). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). 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, BS2, and BP4_moderate. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-1.1

BayesDel_noAF

Benign

-1.2

CADD

Benign

4.7

(source)

DANN

Benign

0.80

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.23

.;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.93

PhyloP100

0.31

PrimateAI

Benign

0.20

PROVEAN

Benign

0.10

.;N

REVEL

Benign

0.059

Sift4G

Benign

0.61

.;T

Vest4

0.028

MPC

0.76

ClinPred

0.00093

GERP RS

-2.2

gMVP

0.0030

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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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