rs1801687

Positions:

chrX-38297424-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001034853.2(RPGR):c.1274G>A(p.Arg425Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,205,424 control chromosomes in the GnomAD database, including 2,698 homozygotes. There are 26,057 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.093 ( 504 hom., 2831 hem., cov: 21)

Exomes 𝑓: 0.063 ( 2194 hom. 23226 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:2

Conservation

PhyloP100: -0.241

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=0.003427893).

BP6

Variant X-38297424-C-T is Benign according to our data. Variant chrX-38297424-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 98734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38297424-C-T is described in Lovd as [Benign]. Variant chrX-38297424-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2 linkuse as main transcript	c.1274G>A	p.Arg425Lys	missense_variant	11/15	ENST00000645032.1	NP_001030025.1	Q92834-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 linkuse as main transcript	c.1274G>A	p.Arg425Lys	missense_variant	11/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-368697C>T		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0932

AC:

10202

AN:

109447

Hom.:

506

Cov.:

AF XY:

0.0886

AC XY:

2822

AN XY:

31837

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.128

Gnomad ASJ

AF:

0.0691

Gnomad EAS

AF:

0.0697

Gnomad SAS

AF:

0.142

Gnomad FIN

AF:

0.0923

Gnomad MID

AF:

0.0603

Gnomad NFE

AF:

0.0491

Gnomad OTH

AF:

0.0791

GnomAD3 exomes

AF:

0.101

AC:

18517

AN:

182620

Hom.:

1026

AF XY:

0.0912

AC XY:

6125

AN XY:

67176

show subpopulations

Gnomad AFR exome

AF:

0.168

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.0633

Gnomad EAS exome

AF:

0.0690

Gnomad SAS exome

AF:

0.151

Gnomad FIN exome

AF:

0.0947

Gnomad NFE exome

AF:

0.0473

Gnomad OTH exome

AF:

0.0746

GnomAD4 exome

AF:

0.0633

AC:

69387

AN:

1095925

Hom.:

2194

Cov.:

AF XY:

0.0642

AC XY:

23226

AN XY:

361895

show subpopulations

Gnomad4 AFR exome

AF:

0.168

Gnomad4 AMR exome

AF:

0.219

Gnomad4 ASJ exome

AF:

0.0609

Gnomad4 EAS exome

AF:

0.0781

Gnomad4 SAS exome

AF:

0.146

Gnomad4 FIN exome

AF:

0.0915

Gnomad4 NFE exome

AF:

0.0462

Gnomad4 OTH exome

AF:

0.0665

GnomAD4 genome

AF:

0.0932

AC:

10210

AN:

109499

Hom.:

504

Cov.:

AF XY:

0.0887

AC XY:

2831

AN XY:

31899

show subpopulations

Gnomad4 AFR

AF:

0.158

Gnomad4 AMR

AF:

0.128

Gnomad4 ASJ

AF:

0.0691

Gnomad4 EAS

AF:

0.0699

Gnomad4 SAS

AF:

0.143

Gnomad4 FIN

AF:

0.0923

Gnomad4 NFE

AF:

0.0491

Gnomad4 OTH

AF:

0.0781

Alfa

AF:

0.0591

Hom.:

3055

Bravo

AF:

0.104

TwinsUK

AF:

0.0472

AC:

175

ALSPAC

AF:

0.0509

AC:

147

ESP6500AA

AF:

0.154

AC:

591

ESP6500EA

AF:

0.0511

AC:

344

ExAC

AF:

0.0972

AC:

11798

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg425Lys in exon 11 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 15.4% (591/3833) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1801687). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -

not provided

Benign:2Other:2

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2014	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

Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.075

DANN

Benign

0.41

DEOGEN2

Benign

0.019

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

FATHMM_MKL

Benign

0.0073

LIST_S2

Benign

0.043

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

MetaRNN

Benign

0.0034

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

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

PrimateAI

Benign

0.26

PROVEAN

Benign

0.15

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

REVEL

Benign

0.0050

Sift

Benign

0.97

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

Sift4G

Benign

0.41

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

Polyphen

0.0

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

Vest4

0.092

MPC

0.021

ClinPred

0.00023

GERP RS

-5.9

Varity_R

0.071

gMVP

0.21

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