rs5963403

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_001034853.2(RPGR):c.552G>T(p.Gln184His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,205,773 control chromosomes in the GnomAD database, including 100 homozygotes. There are 1,194 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.020 ( 46 hom., 604 hem., cov: 23)

Exomes 𝑓: 0.0021 ( 54 hom. 590 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0120

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a repeat RCC1 3 (size 49) in uniprot entity RPGR_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_001034853.2

BP4

Computational evidence support a benign effect (MetaRNN=0.0029917061).

BP6

Variant X-38317383-C-A is Benign according to our data. Variant chrX-38317383-C-A is described in ClinVar as [Benign]. Clinvar id is 255836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2 linkuse as main transcript	c.552G>T	p.Gln184His	missense_variant	6/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1 linkuse as main transcript	c.552G>T	p.Gln184His	missense_variant	6/15		NM_001034853.2	A2	Q92834-6

Frequencies

GnomAD3 genomes

AF:

0.0197

AC:

2201

AN:

111501

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

595

AN XY:

33699

show subpopulations

Gnomad AFR

AF:

0.0687

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00747

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.0106

GnomAD3 exomes

AF:

0.00568

AC:

1041

AN:

183202

Hom.:

AF XY:

0.00359

AC XY:

243

AN XY:

67706

show subpopulations

Gnomad AFR exome

AF:

0.0717

Gnomad AMR exome

AF:

0.00281

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000525

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000856

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00205

AC:

2246

AN:

1094221

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

590

AN XY:

359739

show subpopulations

Gnomad4 AFR exome

AF:

0.0701

Gnomad4 AMR exome

AF:

0.00341

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.00483

GnomAD4 genome

AF:

0.0198

AC:

2211

AN:

111552

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

604

AN XY:

33760

show subpopulations

Gnomad4 AFR

AF:

0.0689

Gnomad4 AMR

AF:

0.00746

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000376

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.0105

Alfa

AF:

0.00304

Hom.:

108

Bravo

AF:

0.0229

ESP6500AA

AF:

0.0730

AC:

280

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00622

AC:

755

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2015	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 04, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.3

DANN

Benign

0.60

DEOGEN2

Benign

0.17

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

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.47

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

MetaRNN

Benign

0.0030

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.5

L;L;L;.;L;L;L;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

0.90

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

REVEL

Benign

0.17

Sift

Benign

0.85

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

Sift4G

Benign

0.35

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

Polyphen

0.0020

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

Vest4

0.14

MutPred

0.60

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);.;Gain of sheet (P = 0.1208);

MVP

0.39

MPC

0.69

ClinPred

0.0015

GERP RS

-3.5

Varity_R

0.16

gMVP

0.50

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