rs62640587

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. BA1PS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.865A>G (p.Ile289Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 289. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001308 among hemizygous individuals, with 51 variant alleles / 389,832 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The variant co-segregates with X-linked retinitis pigmentosa or milder phenotypes in female carriers across 5 meioses in a single family, however, the description of phenotypes is insufficiently detailed to meet PP4 or PP1 (PMID:10482958). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 32531858, 28863407). However, because the variant meets BA1, PS4_Supporting cannot be met. The variant protein exhibits decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID:23213406, PS3_Supporting). The computational predictor REVEL gives the variant a score of 0.553, which is above the ClinGen X-linked IRD VCEP BP4 threshold of <0.290 and below the PP3 threshold of >0.644, so BP4 and PP3 are not met. The computational splicing predictor SpliceAI gives the variant a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP BP4 threshold of <0.2 and indicates that the variant has no predicted impact on splicing. In summary, this variant meets the criteria to be 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 PS3_Supporting. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226452/MONDO:0100437/106

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 1 hom. 44 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:4O:1

Conservation

PhyloP100: 0.0550

Publications

3 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 -7 ACMG points.

PS3

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

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGR	NM_001034853.2	MANE Select	c.865A>G	p.Ile289Val	missense	Exon 8 of 15	NP_001030025.1
RPGR	NM_000328.3		c.865A>G	p.Ile289Val	missense	Exon 8 of 19	NP_000319.1
RPGR	NM_001367245.1		c.862A>G	p.Ile288Val	missense	Exon 8 of 19	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGR	ENST00000645032.1	MANE Select	c.865A>G	p.Ile289Val	missense	Exon 8 of 15	ENSP00000495537.1
RPGR	ENST00000494841.1	TSL:1	n.128A>G		non_coding_transcript_exon	Exon 1 of 4
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-361417T>C		intron	N/A	ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.0000983

AC:

AN:

111869

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000137

AC:

AN:

181885

AF XY:

0.000120

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000402

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000124

AC:

135

AN:

1089955

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

355755

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26253

American (AMR)

AF:

0.00

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.000569

AC:

AN:

19336

East Asian (EAS)

AF:

0.00

AC:

AN:

30134

South Asian (SAS)

AF:

0.00

AC:

AN:

53894

European-Finnish (FIN)

AF:

0.0000494

AC:

AN:

40501

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.000128

AC:

107

AN:

834715

Other (OTH)

AF:

0.000218

AC:

AN:

45812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000983

AC:

AN:

111923

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34077

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30844

American (AMR)

AF:

0.00

AC:

AN:

10488

Ashkenazi Jewish (ASJ)

AF:

0.000377

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00

AC:

AN:

2689

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5998

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53244

Other (OTH)

AF:

0.00

AC:

AN:

1521

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000244

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 03, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RPGR c.865A>G (p.Ile289Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 181885 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RPGR causing Retinitis Pigmentosa, X-Linked (0.00014 vs 0.005), however 8 hemizygotes are present in the gnomad population database, suggesting the variant may benign. c.865A>G has been reported in the literature in individuals affected with Retinitis Pigmentosa, X-Linked including in a family with 2 affected males and 3 female carriers, where only the RPGR gene was tested (Miano_1999, Churchill_2013, Weisschuh_2020). These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa, X-Linked. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

RPGR-related disorder

Benign:1

Sep 23, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Primary ciliary dyskinesia

Benign:1

Nov 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.865A>G (p.Ile289Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 289. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001308 among hemizygous individuals, with 51 variant alleles / 389,832 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The variant co-segregates with X-linked retinitis pigmentosa or milder phenotypes in female carriers across 5 meioses in a single family, however, the description of phenotypes is insufficiently detailed to meet PP4 or PP1 (PMID: 10482958). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 32531858, 28863407). However, because the variant meets BA1, PS4_Supporting cannot be met. The variant protein exhibits decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID: 23213406, PS3_Supporting). The computational predictor REVEL gives the variant a score of 0.553, which is above the ClinGen X-linked IRD VCEP BP4 threshold of <0.290 and below the PP3 threshold of >0.644, so BP4 and PP3 are not met. The computational splicing predictor SpliceAI gives the variant a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP BP4 threshold of <0.2 and indicates that the variant has no predicted impact on splicing. In summary, this variant meets the criteria to be 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 PS3_Supporting. (date of approval 05/16/2025).

Retinitis pigmentosa

Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.0060

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.60

M_CAP

Benign

0.049

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-1.3

PhyloP100

0.055

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.29

REVEL

Uncertain

0.55

Sift

Benign

0.72

Sift4G

Benign

1.0

Polyphen

0.027

Vest4

0.23

MVP

0.81

MPC

0.74

ClinPred

0.039

GERP RS

-2.8

PromoterAI

0.010

Neutral

(source)

Varity_R

0.055

gMVP

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over