rs111631988

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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/Likely benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: 0.0920

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 links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 100560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38322877-T-C is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.223A>G	p.Ile75Val	missense_variant	Exon 3 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.223A>G	p.Ile75Val	missense_variant	Exon 3 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-343244T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0315

AC:

3538

AN:

112158

Hom.:

Cov.:

AF XY:

0.0294

AC XY:

1010

AN XY:

34312

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

GnomAD3 exomes

AF:

0.0159

AC:

2909

AN:

183460

Hom.:

AF XY:

0.0147

AC XY:

998

AN XY:

67914

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 SAS exome

AF:

0.0167

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

Gnomad4 AFR exome

AF:

0.0903

Gnomad4 AMR exome

AF:

0.00861

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.00252

Gnomad4 SAS exome

AF:

0.0140

Gnomad4 FIN exome

AF:

0.00222

Gnomad4 NFE exome

AF:

0.0101

Gnomad4 OTH exome

AF:

0.0149

GnomAD4 genome

AF:

0.0316

AC:

3548

AN:

112209

Hom.:

Cov.:

AF XY:

0.0296

AC XY:

1018

AN XY:

34373

show subpopulations

Gnomad4 AFR

AF:

0.0884

Gnomad4 AMR

AF:

0.0164

Gnomad4 ASJ

AF:

0.0196

Gnomad4 EAS

AF:

0.00445

Gnomad4 SAS

AF:

0.0109

Gnomad4 FIN

AF:

0.00148

Gnomad4 NFE

AF:

0.00930

Gnomad4 OTH

AF:

0.0221

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

Significance: Benign/Likely benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Nov 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NEI Ophthalmic Genomics Laboratory, National Institutes of Health

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Department of Ophthalmology and Visual Sciences Kyoto University

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22995991, 22025579, 9399904, 27884173) -

not specified

Benign:3

May 13, 2015

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.Ile75Val in exon 3 of RPGR: This variant is not expected to have clinical sign ificance because it has been identified in 8.9% (343/3833) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs111631988). -

Jan 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 01, 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. -

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 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.0090

DANN

Benign

0.62

DEOGEN2

Benign

0.11

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

FATHMM_MKL

Benign

0.0049

LIST_S2

Benign

0.35

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

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.93

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

PrimateAI

Benign

0.26

PROVEAN

Benign

0.51

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

REVEL

Benign

0.22

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over