rs144635565

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.1367A>G(p.Gln456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,208,127 control chromosomes in the GnomAD database, including 73 homozygotes. There are 4,533 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0079 ( 2 hom., 224 hem., cov: 22)

Exomes 𝑓: 0.012 ( 71 hom. 4309 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:11

Conservation

PhyloP100: 0.0240

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=0.0034864545).

BP6

Variant X-38297331-T-C is Benign according to our data. Variant chrX-38297331-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 92850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38297331-T-C is described in Lovd as [Benign]. Variant chrX-38297331-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00787 (869/110357) while in subpopulation NFE AF= 0.0127 (673/52932). AF 95% confidence interval is 0.0119. There are 2 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.1367A>G	p.Gln456Arg	missense_variant	Exon 11 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.1367A>G	p.Gln456Arg	missense_variant	Exon 11 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-368790T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00788

AC:

869

AN:

110303

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

224

AN XY:

32513

show subpopulations

Gnomad AFR

AF:

0.00207

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00598

Gnomad ASJ

AF:

0.000759

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00351

Gnomad FIN

AF:

0.00943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0127

Gnomad OTH

AF:

0.00473

GnomAD3 exomes

AF:

0.00831

AC:

1524

AN:

183345

Hom.:

AF XY:

0.00796

AC XY:

540

AN XY:

67837

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00248

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00398

Gnomad FIN exome

AF:

0.0108

Gnomad NFE exome

AF:

0.0140

Gnomad OTH exome

AF:

0.00773

GnomAD4 exome

AF:

0.0124

AC:

13585

AN:

1097770

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

4309

AN XY:

363160

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00256

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00495

Gnomad4 FIN exome

AF:

0.0120

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.00964

GnomAD4 genome

AF:

0.00787

AC:

869

AN:

110357

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

224

AN XY:

32577

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.00598

Gnomad4 ASJ

AF:

0.000759

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00353

Gnomad4 FIN

AF:

0.00943

Gnomad4 NFE

AF:

0.0127

Gnomad4 OTH

AF:

0.00466

Alfa

AF:

0.0115

Hom.:

505

Bravo

AF:

0.00682

TwinsUK

AF:

0.0159

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00209

AC:

ESP6500EA

AF:

0.0106

AC:

ExAC

AF:

0.00889

AC:

1079

EpiCase

AF:

0.0118

EpiControl

AF:

0.00878

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Apr 12, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 30, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 30, 2013

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.Gln456Arg in exon 11 of RPGR: This variant is not expected to have clinical significance because it has been identified in 1.1% (71/6728) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs144635565). -

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

- -

May 27, 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. -

Retinal dystrophy

Uncertain:1

Jan 01, 2009

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.86

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.42

DANN

Benign

0.44

DEOGEN2

Benign

0.031

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

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.24

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

MetaRNN

Benign

0.0035

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

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

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.23

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

REVEL

Benign

0.016

Sift

Benign

0.46

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

Sift4G

Benign

0.55

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

Polyphen

0.0030

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

Vest4

0.035

MVP

0.082

MPC

0.022

ClinPred

0.0019

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.064

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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