rs144635565

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1BP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001034853.2(RPGR):c.1367A>G (p.Gln456Arg) variant is a missense variant encoding the substitution of Glutamine with Arginine at amino acid 456. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01145 among hemizygous individuals, with 4533 variant alleles / 395737 hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in three probands with an alternate molecular basis for the disease (PMIDs: 18552978, 22334370, 11992260). However, the BP5 code is considered not applicable for RPGR-related retinopathy. The computational predictor REVEL gives a score of 0.016, 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 0.08, 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 ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1 and BP4_strong. (VCEP specifications version 1.0.0; date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146033/MONDO:0100437/106

Frequency

Genomes: 𝑓 0.0079 ( 2 hom., 224 hem., cov: 22)

Exomes 𝑓: 0.012 ( 71 hom. 4309 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:12

Conservation

PhyloP100: 0.0240

Publications

9 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 -12 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.1367A>G	p.Gln456Arg	missense_variant	Exon 11 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.1367A>G	p.Gln456Arg	missense_variant	Exon 11 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-368790T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00788

AC:

869

AN:

110303

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00598

Gnomad ASJ

AF:

0.000759

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00351

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00473

GnomAD2 exomes

AF:

0.00831

AC:

1524

AN:

183345

AF XY:

0.00796

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00248

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00773

GnomAD4 exome

AF:

0.0124

AC:

13585

AN:

1097770

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

4309

AN XY:

363160

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

26394

American (AMR)

AF:

0.00256

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30188

South Asian (SAS)

AF:

0.00495

AC:

268

AN:

54140

European-Finnish (FIN)

AF:

0.0120

AC:

485

AN:

40523

Middle Eastern (MID)

AF:

0.00169

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.0145

AC:

12238

AN:

841742

Other (OTH)

AF:

0.00964

AC:

444

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

479

958

1438

1917

2396

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

460

920

1380

1840

2300

<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:

0.00787

AC:

869

AN:

110357

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

224

AN XY:

32577

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

30430

American (AMR)

AF:

0.00598

AC:

AN:

10209

Ashkenazi Jewish (ASJ)

AF:

0.000759

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3471

South Asian (SAS)

AF:

0.00353

AC:

AN:

2552

European-Finnish (FIN)

AF:

0.00943

AC:

AN:

5726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0127

AC:

673

AN:

52932

Other (OTH)

AF:

0.00466

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0108

Hom.:

512

Bravo

AF:

0.00682

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00889

AC:

1079

EpiCase

AF:

0.0118

EpiControl

AF:

0.00878

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:12

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 12, 2022

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 30, 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.Gln456Arg in exon 11 of RPGR: This variant is not expected to have clinical significance because it has been identified in 1.1% (71/6728) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144635565). -

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

- -

May 27, 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. -

Retinal dystrophy

Uncertain:1

Jan 01, 2009

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

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

The NM_001034853.2(RPGR):c.1367A>G (p.Gln456Arg) variant is a missense variant encoding the substitution of Glutamine with Arginine at amino acid 456. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01145 among hemizygous individuals, with 4533 variant alleles / 395737 hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in three probands with an alternate molecular basis for the disease (PMIDs: 18552978, 22334370, 11992260). However, the BP5 code is considered not applicable for RPGR-related retinopathy. The computational predictor REVEL gives a score of 0.016, 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 0.08, 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 ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1 and BP4_strong. (VCEP specifications version 1.0.0; date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.42

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.031

.;.;T;.;.;.;.

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.24

.;T;T;T;T;.;T

MetaRNN

Benign

0.0035

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

N;N;N;.;.;N;N

PhyloP100

0.024

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.23

N;.;N;.;.;.;N

REVEL

Benign

0.016

Sift

Benign

0.46

T;.;T;.;.;.;.

Sift4G

Benign

0.55

T;.;T;.;.;.;T

Polyphen

0.0030

B;B;.;.;.;.;.

Vest4

0.035

MVP

0.082

MPC

0.022

ClinPred

0.0019

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.11

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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