rs199663434

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP3

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.2667_2669del (p.Glu890del) is a short in-frame deletion of 3 base pairs that encode amino acid 890 within a low-complexity region (PMID:27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v.4.1.0 at a frequency of 0.1323 among hemizygous individuals, with 6,699 variant alleles / 50,616 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). 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 BP3. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385255/MONDO:0100437/106

Frequency

Genomes: 𝑓 0.090 ( 61 hom., 12 hem., cov: 2)

Exomes 𝑓: 0.046 ( 1857 hom. 6687 hem. )

Consequence

RPGR
NM_001034853.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: 0.0900

Publications

6 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.

BP3

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.2667_2669delGGA	p.Glu890del	disruptive_inframe_deletion	Exon 15 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.2667_2669delGGA	p.Glu890del	disruptive_inframe_deletion	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1 link	c.172-379789_172-379787delCTC		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes

AF:

0.0900

AC:

798

AN:

8868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0633

Gnomad AMI

AF:

0.0698

Gnomad AMR

AF:

0.0564

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0164

Gnomad FIN

AF:

0.0707

Gnomad MID

AF:

0.182

Gnomad NFE

AF:

0.111

Gnomad OTH

AF:

0.130

GnomAD2 exomes

AF:

0.0144

AC:

611

AN:

42549

AF XY:

0.00601

show subpopulations

Gnomad AFR exome

AF:

0.0237

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.0171

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000852

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0463

AC:

27313

AN:

589351

Hom.:

1857

AF XY:

0.0467

AC XY:

6687

AN XY:

143085

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0317

AC:

426

AN:

13436

American (AMR)

AF:

0.0379

AC:

540

AN:

14244

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

1277

AN:

8440

East Asian (EAS)

AF:

0.000392

AC:

AN:

5098

South Asian (SAS)

AF:

0.0151

AC:

481

AN:

31924

European-Finnish (FIN)

AF:

0.193

AC:

1811

AN:

9384

Middle Eastern (MID)

AF:

0.121

AC:

165

AN:

1361

European-Non Finnish (NFE)

AF:

0.0432

AC:

20886

AN:

482948

Other (OTH)

AF:

0.0766

AC:

1725

AN:

22516

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.374

Heterozygous variant carriers

720

1440

2159

2879

3599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.0900

AC:

798

AN:

8867

Hom.:

Cov.:

AF XY:

0.0334

AC XY:

AN XY:

359

show subpopulations

African (AFR)

AF:

0.0633

AC:

122

AN:

1928

American (AMR)

AF:

0.0566

AC:

AN:

760

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

AN:

233

East Asian (EAS)

AF:

0.00

AC:

AN:

277

South Asian (SAS)

AF:

0.0169

AC:

AN:

European-Finnish (FIN)

AF:

0.0707

AC:

AN:

396

Middle Eastern (MID)

AF:

0.182

AC:

AN:

European-Non Finnish (NFE)

AF:

0.111

AC:

558

AN:

5035

Other (OTH)

AF:

0.128

AC:

AN:

125

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.418

Heterozygous variant carriers

106

132

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:

0.00562

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:5

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: MAF -

Jan 29, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

not provided

Benign:1

Aug 12, 2019

GeneDx

Significance:Likely 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.2667_2669del (p.Glu890del) is a short in-frame deletion of 3 base pairs that encode amino acid 890 within a low-complexity region (PMID: 27162334) that extends approximately from amino acids 787–1043 in RPGR (BP3). This variant is present in gnomAD v.4.1.0 at a frequency of 0.1323 among hemizygous individuals, with 6,699 variant alleles / 50,616 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). 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 BP3. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.090

Mutation Taster

=81/19

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