rs1801688

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The NM_001034853.2(RPGR):c.1697G>A (p.Gly566Glu) variant is a missense variant encoding the substitution of Glycine with Glutamic acid at amino acid 566. This variant is present in gnomAD v.4.1.0 at a frequency of 0.06732 among hemizygous individuals, with 26691 variant alleles / 396470 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant was shown to have normal protein function and localization (PMID:30622176). The computational predictor REVEL gives a score of 0.063, 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 0.05, 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 likely 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_moderate (date of approval 05/15/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146040/MONDO:0100437/106

Frequency

Genomes: 𝑓 0.096 ( 525 hom., 3170 hem., cov: 23)

Exomes 𝑓: 0.064 ( 2209 hom. 23521 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:10O:1

Conservation

PhyloP100: -0.0420

Publications

14 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 -9 ACMG points.

BP4

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.1697G>A	p.Gly566Glu	missense_variant	Exon 14 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 link	c.1697G>A	p.Gly566Glu	missense_variant	Exon 14 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1 link	c.172-378204C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.0956

AC:

10649

AN:

111340

Hom.:

527

Cov.:

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.209

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.0691

Gnomad EAS

AF:

0.0728

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.0944

Gnomad MID

AF:

0.0549

Gnomad NFE

AF:

0.0490

Gnomad OTH

AF:

0.0745

GnomAD2 exomes

AF:

0.102

AC:

18602

AN:

182454

AF XY:

0.0921

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.0628

Gnomad EAS exome

AF:

0.0698

Gnomad FIN exome

AF:

0.0956

Gnomad NFE exome

AF:

0.0475

Gnomad OTH exome

AF:

0.0751

GnomAD4 exome

AF:

0.0636

AC:

69762

AN:

1097383

Hom.:

2209

Cov.:

AF XY:

0.0648

AC XY:

23521

AN XY:

362827

show subpopulations

African (AFR)

AF:

0.175

AC:

4604

AN:

26367

American (AMR)

AF:

0.220

AC:

7726

AN:

35154

Ashkenazi Jewish (ASJ)

AF:

0.0608

AC:

1176

AN:

19354

East Asian (EAS)

AF:

0.0784

AC:

2367

AN:

30197

South Asian (SAS)

AF:

0.147

AC:

7939

AN:

53985

European-Finnish (FIN)

AF:

0.0913

AC:

3694

AN:

40480

Middle Eastern (MID)

AF:

0.0666

AC:

275

AN:

4131

European-Non Finnish (NFE)

AF:

0.0462

AC:

38897

AN:

841644

Other (OTH)

AF:

0.0669

AC:

3084

AN:

46071

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

2203

4407

6610

8814

11017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1726

3452

5178

6904

8630

<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:

0.0957

AC:

10655

AN:

111393

Hom.:

525

Cov.:

AF XY:

0.0942

AC XY:

3170

AN XY:

33643

show subpopulations

African (AFR)

AF:

0.165

AC:

5037

AN:

30616

American (AMR)

AF:

0.130

AC:

1368

AN:

10501

Ashkenazi Jewish (ASJ)

AF:

0.0691

AC:

182

AN:

2634

East Asian (EAS)

AF:

0.0730

AC:

260

AN:

3562

South Asian (SAS)

AF:

0.144

AC:

382

AN:

2645

European-Finnish (FIN)

AF:

0.0944

AC:

557

AN:

5898

Middle Eastern (MID)

AF:

0.0509

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0490

AC:

2605

AN:

53123

Other (OTH)

AF:

0.0730

AC:

111

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

325

649

974

1298

1623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0637

Hom.:

4290

Bravo

AF:

0.106

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0505

AC:

146

ESP6500AA

AF:

0.160

AC:

614

ESP6500EA

AF:

0.0508

AC:

342

ExAC

AF:

0.0978

AC:

11879

EpiCase

AF:

0.0465

EpiControl

AF:

0.0459

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Oct 03, 2013

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.Gly566Glu in exon 14 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 16.0% (614/3833) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1801688). -

not provided

Benign:2Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:2

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. -

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

The NM_001034853.2(RPGR):c.1697G>A (p.Gly566Glu) variant is a missense variant encoding the substitution of Glycine with Glutamic acid at amino acid 566. This variant is present in gnomAD v.4.1.0 at a frequency of 0.06732 among hemizygous individuals, with 26691 variant alleles / 396470 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant was shown to have normal protein function and localization (PMID: 30622176). The computational predictor REVEL gives a score of 0.063, 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 0.05, 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 likely 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_moderate (date of approval 05/15/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.045

.;.;T;.;.;.

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.41

.;T;T;T;.;T

MetaRNN

Benign

0.0034

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;L;.;L;L

PhyloP100

-0.042

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.6

D;.;N;.;.;D

REVEL

Benign

0.063

Sift

Pathogenic

0.0

D;.;T;.;.;.

Sift4G

Benign

0.40

T;.;T;.;.;T

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.22

MPC

0.13

ClinPred

0.028

GERP RS

0.80

Varity_R

0.091

gMVP

0.075

Mutation Taster

=100/0

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