rs62640587

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PS1_ModeratePM1BP4_StrongBS2

The NM_001034853.2(RPGR):c.865A>G(p.Ile289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,201,878 control chromosomes in the GnomAD database, including 1 homozygotes. There are 51 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 1 hom. 44 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3O:1

Conservation

PhyloP100: 0.0550

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 Likely_benign. Variant got -4 ACMG points.

PS1

Transcript NM_001034853.2 (RPGR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a repeat RCC1 5 (size 51) in uniprot entity RPGR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001034853.2

BP4

Computational evidence support a benign effect (MetaRNN=0.06523895).

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2 linkuse as main transcript	c.865A>G	p.Ile289Val	missense_variant	8/15	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.865A>G	p.Ile289Val	missense_variant	8/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-361417T>C		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0000983

AC:

AN:

111869

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

AN XY:

34013

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.000150

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

181885

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

66565

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000402

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000260

Gnomad OTH exome

AF:

0.000222

GnomAD4 exome

AF:

0.000124

AC:

135

AN:

1089955

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

355755

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000569

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000494

Gnomad4 NFE exome

AF:

0.000128

Gnomad4 OTH exome

AF:

0.000218

GnomAD4 genome

AF:

0.0000983

AC:

AN:

111923

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

AN XY:

34077

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000377

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 03, 2022

Variant summary: RPGR c.865A>G (p.Ile289Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 181885 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RPGR causing Retinitis Pigmentosa, X-Linked (0.00014 vs 0.005), however 8 hemizygotes are present in the gnomad population database, suggesting the variant may benign. c.865A>G has been reported in the literature in individuals affected with Retinitis Pigmentosa, X-Linked including in a family with 2 affected males and 3 female carriers, where only the RPGR gene was tested (Miano_1999, Churchill_2013, Weisschuh_2020). These reports do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa, X-Linked. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

RPGR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

- -

Retinitis pigmentosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

not provided

Other:1

not provided, no classification provided

literature only

Retina International

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.0060

DANN

Benign

0.65

DEOGEN2

Benign

0.16

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

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.60

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

M_CAP

Benign

0.049

MetaRNN

Benign

0.065

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

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-1.3

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.29

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

REVEL

Uncertain

0.55

Sift

Benign

0.72

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

Sift4G

Benign

1.0

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

Polyphen

0.027

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

Vest4

0.23

MVP

0.81

MPC

0.74

ClinPred

0.039

GERP RS

-2.8

Varity_R

0.055

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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