rs41305223

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.1033A>G(p.Asn345Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,203,141 control chromosomes in the GnomAD database, including 51 homozygotes. There are 3,751 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.0071 ( 2 hom., 204 hem., cov: 22)

Exomes 𝑓: 0.010 ( 49 hom. 3547 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:6O:1

Conservation

PhyloP100: 0.789

Publications

8 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=0.0090559125).

BP6

Variant X-38301273-T-C is Benign according to our data. Variant chrX-38301273-T-C is described in ClinVar as Benign. ClinVar VariationId is 98725.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00709 (790/111478) while in subpopulation NFE AF = 0.0117 (622/53079). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 790 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.1033A>G	p.Asn345Asp	missense_variant	Exon 9 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.1033A>G	p.Asn345Asp	missense_variant	Exon 9 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-364848T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

791

AN:

111428

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00325

Gnomad ASJ

AF:

0.00228

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00150

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00667

GnomAD2 exomes

AF:

0.00706

AC:

1268

AN:

179715

AF XY:

0.00660

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00920

GnomAD4 exome

AF:

0.0104

AC:

11320

AN:

1091663

Hom.:

Cov.:

AF XY:

0.00992

AC XY:

3547

AN XY:

357487

show subpopulations

African (AFR)

AF:

0.000875

AC:

AN:

26282

American (AMR)

AF:

0.00310

AC:

109

AN:

35151

Ashkenazi Jewish (ASJ)

AF:

0.00290

AC:

AN:

19341

East Asian (EAS)

AF:

0.00

AC:

AN:

30115

South Asian (SAS)

AF:

0.00195

AC:

105

AN:

53759

European-Finnish (FIN)

AF:

0.00742

AC:

300

AN:

40432

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

4116

European-Non Finnish (NFE)

AF:

0.0124

AC:

10345

AN:

836603

Other (OTH)

AF:

0.00822

AC:

377

AN:

45864

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

343

686

1028

1371

1714

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<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:

0.00709

AC:

790

AN:

111478

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

204

AN XY:

33718

show subpopulations

African (AFR)

AF:

0.00225

AC:

AN:

30686

American (AMR)

AF:

0.00325

AC:

AN:

10473

Ashkenazi Jewish (ASJ)

AF:

0.00228

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3558

South Asian (SAS)

AF:

0.00151

AC:

AN:

2650

European-Finnish (FIN)

AF:

0.00754

AC:

AN:

5972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0117

AC:

622

AN:

53079

Other (OTH)

AF:

0.00658

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

100

134

167

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:

0.00982

Hom.:

487

Bravo

AF:

0.00635

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00760

AC:

922

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Nov 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10937588, 11857109) -

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

- -

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 15, 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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RPGR-related retinopathy

Benign:1

Aug 01, 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.1033A>G (p.Asn345Asp) is a missense variant predicted to cause substitution of asparagine by aspartic acid at amino acid 345. This variant is present in gnomAD v4.1.0 at a frequency of 0.009588 among hemizygous individuals, with 3,751 variant alleles / 391,205 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.241, which is below the ClinGen X-linked IRD VCEP threshold of <0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.01, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). 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. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.7

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.43

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

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.67

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

MetaRNN

Benign

0.0091

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

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.2

L;L;L;.;L;L;L;.

PhyloP100

0.79

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

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

REVEL

Benign

0.24

Sift

Benign

0.34

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

Sift4G

Benign

0.40

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

Polyphen

0.020

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

Vest4

0.12

MVP

0.64

MPC

1.1

ClinPred

0.013

GERP RS

-3.1

PromoterAI

0.013

Neutral

(source)

Varity_R

0.25

gMVP

0.76

Mutation Taster

=96/4

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