rs1801688

Positions:

chrX-38287917-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.1697G>A(p.Gly566Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 1,208,776 control chromosomes in the GnomAD database, including 2,734 homozygotes. There are 26,691 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.096 ( 525 hom., 3170 hem., cov: 23)

Exomes 𝑓: 0.064 ( 2209 hom. 23521 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -0.0420

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=0.0034307837).

BP6

Variant X-38287917-C-T is Benign according to our data. Variant chrX-38287917-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38287917-C-T is described in Lovd as [Benign]. Variant chrX-38287917-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 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.1697G>A	p.Gly566Glu	missense_variant	14/15	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.1697G>A	p.Gly566Glu	missense_variant	14/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-378204C>T		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0956

AC:

10649

AN:

111340

Hom.:

527

Cov.:

AF XY:

0.0942

AC XY:

3163

AN XY:

33578

show subpopulations

Gnomad AFR

AF:

0.165

Gnomad AMI

AF:

0.209

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.0691

Gnomad EAS

AF:

0.0728

Gnomad SAS

AF:

0.144

Gnomad FIN

AF:

0.0944

Gnomad MID

AF:

0.0549

Gnomad NFE

AF:

0.0490

Gnomad OTH

AF:

0.0745

GnomAD3 exomes

AF:

0.102

AC:

18602

AN:

182454

Hom.:

1038

AF XY:

0.0921

AC XY:

6171

AN XY:

67034

show subpopulations

Gnomad AFR exome

AF:

0.174

Gnomad AMR exome

AF:

0.232

Gnomad ASJ exome

AF:

0.0628

Gnomad EAS exome

AF:

0.0698

Gnomad SAS exome

AF:

0.149

Gnomad FIN exome

AF:

0.0956

Gnomad NFE exome

AF:

0.0475

Gnomad OTH exome

AF:

0.0751

GnomAD4 exome

AF:

0.0636

AC:

69762

AN:

1097383

Hom.:

2209

Cov.:

AF XY:

0.0648

AC XY:

23521

AN XY:

362827

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.220

Gnomad4 ASJ exome

AF:

0.0608

Gnomad4 EAS exome

AF:

0.0784

Gnomad4 SAS exome

AF:

0.147

Gnomad4 FIN exome

AF:

0.0913

Gnomad4 NFE exome

AF:

0.0462

Gnomad4 OTH exome

AF:

0.0669

GnomAD4 genome

AF:

0.0957

AC:

10655

AN:

111393

Hom.:

525

Cov.:

AF XY:

0.0942

AC XY:

3170

AN XY:

33643

show subpopulations

Gnomad4 AFR

AF:

0.165

Gnomad4 AMR

AF:

0.130

Gnomad4 ASJ

AF:

0.0691

Gnomad4 EAS

AF:

0.0730

Gnomad4 SAS

AF:

0.144

Gnomad4 FIN

AF:

0.0944

Gnomad4 NFE

AF:

0.0490

Gnomad4 OTH

AF:

0.0730

Alfa

AF:

0.0571

Hom.:

3325

Bravo

AF:

0.106

TwinsUK

AF:

0.0461

AC:

171

ALSPAC

AF:

0.0505

AC:

146

ESP6500AA

AF:

0.160

AC:

614

ESP6500EA

AF:

0.0508

AC:

342

ExAC

AF:

0.0978

AC:

11879

EpiCase

AF:

0.0465

EpiControl

AF:

0.0459

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -
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.Gly566Glu in exon 14 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 16.0% (614/3833) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1801688). -

not provided

Benign:2Other:1

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

0.12

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.74

DEOGEN2

Benign

0.045

.;.;T;.;.;.

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.41

.;T;T;T;.;T

MetaRNN

Benign

0.0034

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L;L;.;L;L

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.6

D;.;N;.;.;D

REVEL

Benign

0.063

Sift

Pathogenic

0.0

D;.;T;.;.;.

Sift4G

Benign

0.40

T;.;T;.;.;T

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.22

MPC

0.13

ClinPred

0.028

GERP RS

0.80

Varity_R

0.091

gMVP

0.075

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