rs41312104

Positions:

chrX-38288016-G-A

Variant summary

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

The NM_001034853.2(RPGR):c.1598C>T(p.Thr533Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,207,527 control chromosomes in the GnomAD database, including 288 homozygotes. There are 8,907 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.020 ( 38 hom., 621 hem., cov: 22)

Exomes 𝑓: 0.024 ( 250 hom. 8286 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0500

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=0.0017929971).

BP6

Variant X-38288016-G-A is Benign according to our data. Variant chrX-38288016-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38288016-G-A is described in Lovd as [Likely_benign]. Variant chrX-38288016-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0199 (2225/111643) while in subpopulation NFE AF= 0.029 (1540/53134). AF 95% confidence interval is 0.0278. There are 38 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.1598C>T	p.Thr533Met	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 link	c.1598C>T	p.Thr533Met	missense_variant	14/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-378105G>A		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0199

AC:

2225

AN:

111591

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

620

AN XY:

33833

show subpopulations

Gnomad AFR

AF:

0.00365

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.0439

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00150

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.0420

Gnomad NFE

AF:

0.0290

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0189

AC:

3446

AN:

182733

Hom.:

AF XY:

0.0182

AC XY:

1227

AN XY:

67421

show subpopulations

Gnomad AFR exome

AF:

0.00411

Gnomad AMR exome

AF:

0.0126

Gnomad ASJ exome

AF:

0.0439

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00310

Gnomad FIN exome

AF:

0.0196

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0288

GnomAD4 exome

AF:

0.0238

AC:

26108

AN:

1095884

Hom.:

250

Cov.:

AF XY:

0.0229

AC XY:

8286

AN XY:

362224

show subpopulations

Gnomad4 AFR exome

AF:

0.00379

Gnomad4 AMR exome

AF:

0.0132

Gnomad4 ASJ exome

AF:

0.0410

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00346

Gnomad4 FIN exome

AF:

0.0214

Gnomad4 NFE exome

AF:

0.0268

Gnomad4 OTH exome

AF:

0.0229

GnomAD4 genome

AF:

0.0199

AC:

2225

AN:

111643

Hom.:

Cov.:

AF XY:

0.0183

AC XY:

621

AN XY:

33895

show subpopulations

Gnomad4 AFR

AF:

0.00364

Gnomad4 AMR

AF:

0.0160

Gnomad4 ASJ

AF:

0.0439

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00150

Gnomad4 FIN

AF:

0.0192

Gnomad4 NFE

AF:

0.0290

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0278

Hom.:

1219

Bravo

AF:

0.0190

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0322

AC:

ESP6500AA

AF:

0.00339

AC:

ESP6500EA

AF:

0.0293

AC:

197

ExAC

AF:

0.0195

AC:

2362

EpiCase

AF:

0.0281

EpiControl

AF:

0.0287

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Thr533Met in exon 14 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (197/6728) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41312104). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.015

DANN

Benign

0.78

DEOGEN2

Benign

0.021

.;.;T;.;.;.

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.48

.;T;T;T;.;T

MetaRNN

Benign

0.0018

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.79

N;N;N;.;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

1.1

N;.;N;.;.;N

REVEL

Benign

0.015

Sift

Benign

0.16

T;.;T;.;.;.

Sift4G

Benign

0.14

T;.;T;.;.;T

Polyphen

0.27

B;B;.;.;.;.

Vest4

0.061

MPC

0.022

ClinPred

0.0098

GERP RS

-3.7

Varity_R

0.012

gMVP

0.061

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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