rs150549982

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: NM_001034853.2(RPGR):c.1240G>C is a missense variant predicted to cause the substitution of glutamate by glutamine at amino acid 414. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00008303 among hemizygous individuals, with 33 variant alleles / 397,426 total 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 0.119, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on the RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.02, 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 benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1, and BP4_moderate. (VCEP specifications version 1.0.0; date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385514/MONDO:0100437/106

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.000059 ( 0 hom. 22 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: 4.09

Publications

1 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.1240G>C	p.Glu414Gln	missense_variant	Exon 10 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.1240G>C	p.Glu414Gln	missense_variant	Exon 10 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-367160C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

111966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000158

AC:

AN:

183397

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00182

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1097871

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

363247

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

26402

American (AMR)

AF:

0.000170

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19380

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00

AC:

AN:

54138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841804

Other (OTH)

AF:

0.000195

AC:

AN:

46083

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.000473

AC:

AN:

112019

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

34179

show subpopulations

African (AFR)

AF:

0.00169

AC:

AN:

30845

American (AMR)

AF:

0.00

AC:

AN:

10529

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3598

South Asian (SAS)

AF:

0.00

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6042

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53238

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000285

Hom.:

Bravo

AF:

0.000536

ESP6500AA

AF:

0.000783

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000198

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 16, 2018

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked cone-rod dystrophy 1;C1845667:Retinitis pigmentosa 3;C2749137:Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness;C3151784:Macular degeneration, X-linked atrophic

Benign:1

Nov 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:1

Jan 27, 2025

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.1240G>C is a missense variant predicted to cause the substitution of glutamate by glutamine at amino acid 414. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00008303 among hemizygous individuals, with 33 variant alleles / 397,426 total 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 0.119, which is below the ClinGen X-linked IRD VCEP threshold of < 0.183 and predicts a non-damaging effect on the RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.02, 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 benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1, and BP4_moderate. (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

0.24

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

.;.;T;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

.;D;D;.;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.014

T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.6

M;M;M;M;M

PhyloP100

4.1

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.4

N;.;N;.;D

REVEL

Benign

0.12

Sift

Benign

0.082

T;.;D;.;.

Sift4G

Benign

0.073

T;.;D;.;D

Polyphen

1.0

D;D;.;.;.

Vest4

0.48

MVP

0.42

MPC

0.17

ClinPred

0.042

GERP RS

5.3

Varity_R

0.47

gMVP

0.50

Mutation Taster

=90/10

polymorphism

(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