rs111631988

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001034853.2(RPGR):c.223A>G(p.Ile75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,208,675 control chromosomes in the GnomAD database, including 224 homozygotes. There are 5,304 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 0.032 ( 85 hom., 1018 hem., cov: 23)

Exomes 𝑓: 0.012 ( 139 hom. 4286 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:11O:1

Conservation

PhyloP100: 0.0920

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020298362).

BP6

Variant X-38322877-T-C is Benign according to our data. Variant chrX-38322877-T-C is described in ClinVar as Benign. ClinVar VariationId is 100560.Status of the report is reviewed_by_expert_panel, 3 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

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.223A>G	p.Ile75Val	missense	Exon 3 of 15	NP_001030025.1
RPGR	NM_000328.3		c.223A>G	p.Ile75Val	missense	Exon 3 of 19	NP_000319.1
RPGR	NM_001367245.1		c.223A>G	p.Ile75Val	missense	Exon 3 of 19	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGR	ENST00000645032.1	MANE Select	c.223A>G	p.Ile75Val	missense	Exon 3 of 15	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-343244T>C		intron	N/A	ENSP00000417050.1
RPGR	ENST00000339363.7	TSL:5	c.223A>G	p.Ile75Val	missense	Exon 3 of 18	ENSP00000343671.3

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

3538

AN:

112158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0882

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.00444

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00148

Gnomad MID

AF:

0.0385

Gnomad NFE

AF:

0.00930

Gnomad OTH

AF:

0.0217

GnomAD2 exomes

AF:

0.0159

AC:

2909

AN:

183460

AF XY:

0.0147

show subpopulations

Gnomad AFR exome

AF:

0.0958

Gnomad AMR exome

AF:

0.00769

Gnomad ASJ exome

AF:

0.0210

Gnomad EAS exome

AF:

0.00649

Gnomad FIN exome

AF:

0.00175

Gnomad NFE exome

AF:

0.00955

Gnomad OTH exome

AF:

0.0135

GnomAD4 exome

AF:

0.0121

AC:

13283

AN:

1096466

Hom.:

139

Cov.:

AF XY:

0.0118

AC XY:

4286

AN XY:

362086

show subpopulations

African (AFR)

AF:

0.0903

AC:

2379

AN:

26357

American (AMR)

AF:

0.00861

AC:

303

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

373

AN:

19356

East Asian (EAS)

AF:

0.00252

AC:

AN:

30129

South Asian (SAS)

AF:

0.0140

AC:

757

AN:

54108

European-Finnish (FIN)

AF:

0.00222

AC:

AN:

40525

Middle Eastern (MID)

AF:

0.0281

AC:

116

AN:

4128

European-Non Finnish (NFE)

AF:

0.0101

AC:

8503

AN:

840627

Other (OTH)

AF:

0.0149

AC:

686

AN:

46031

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

413

825

1238

1650

2063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.0316

AC:

3548

AN:

112209

Hom.:

Cov.:

AF XY:

0.0296

AC XY:

1018

AN XY:

34373

show subpopulations

African (AFR)

AF:

0.0884

AC:

2729

AN:

30880

American (AMR)

AF:

0.0164

AC:

174

AN:

10578

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

2653

East Asian (EAS)

AF:

0.00445

AC:

AN:

3593

South Asian (SAS)

AF:

0.0109

AC:

AN:

2750

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

6078

Middle Eastern (MID)

AF:

0.0425

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.00930

AC:

495

AN:

53242

Other (OTH)

AF:

0.0221

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

125

251

376

502

627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0126

Hom.:

542

Bravo

AF:

0.0357

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00692

AC:

ESP6500AA

AF:

0.0895

AC:

343

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.0168

AC:

2044

EpiCase

AF:

0.0106

EpiControl

AF:

0.0112

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Primary ciliary dyskinesia (2)

RPGR-related retinopathy (1)

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.0090

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.11

FATHMM_MKL

Benign

0.0049

LIST_S2

Benign

0.35

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.93

PhyloP100

0.092

PrimateAI

Benign

0.26

PROVEAN

Benign

0.51

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.048

MPC

0.60

ClinPred

0.0064

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.066

gMVP

0.78

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over