X-38297407-T-C

Position:

chrX-38297407-T-C

Variant summary

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

The NM_001034853.2(RPGR):c.1291A>G(p.Ile431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,206,088 control chromosomes in the GnomAD database, including 1,621 homozygotes. There are 16,241 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.061 ( 269 hom., 1895 hem., cov: 22)

Exomes 𝑓: 0.037 ( 1352 hom. 14346 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -2.15

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=0.001911819).

BP6

Variant X-38297407-T-C is Benign according to our data. Variant chrX-38297407-T-C is described in ClinVar as [Benign]. Clinvar id is 98737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38297407-T-C is described in Lovd as [Benign]. Variant chrX-38297407-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 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.1291A>G	p.Ile431Val	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.1291A>G	p.Ile431Val	missense_variant	11/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-368714T>C		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0613

AC:

6730

AN:

109759

Hom.:

270

Cov.:

AF XY:

0.0589

AC XY:

1887

AN XY:

32045

show subpopulations

Gnomad AFR

AF:

0.115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.106

Gnomad ASJ

AF:

0.0247

Gnomad EAS

AF:

0.0690

Gnomad SAS

AF:

0.139

Gnomad FIN

AF:

0.0725

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.0198

Gnomad OTH

AF:

0.0543

GnomAD3 exomes

AF:

0.0786

AC:

14382

AN:

182938

Hom.:

820

AF XY:

0.0701

AC XY:

4728

AN XY:

67446

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.216

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.0696

Gnomad SAS exome

AF:

0.147

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.0195

Gnomad OTH exome

AF:

0.0434

GnomAD4 exome

AF:

0.0375

AC:

41071

AN:

1096274

Hom.:

1352

Cov.:

AF XY:

0.0396

AC XY:

14346

AN XY:

362000

show subpopulations

Gnomad4 AFR exome

AF:

0.124

Gnomad4 AMR exome

AF:

0.202

Gnomad4 ASJ exome

AF:

0.0191

Gnomad4 EAS exome

AF:

0.0784

Gnomad4 SAS exome

AF:

0.143

Gnomad4 FIN exome

AF:

0.0695

Gnomad4 NFE exome

AF:

0.0184

Gnomad4 OTH exome

AF:

0.0402

GnomAD4 genome

AF:

0.0613

AC:

6737

AN:

109814

Hom.:

269

Cov.:

AF XY:

0.0590

AC XY:

1895

AN XY:

32110

show subpopulations

Gnomad4 AFR

AF:

0.115

Gnomad4 AMR

AF:

0.106

Gnomad4 ASJ

AF:

0.0247

Gnomad4 EAS

AF:

0.0692

Gnomad4 SAS

AF:

0.139

Gnomad4 FIN

AF:

0.0725

Gnomad4 NFE

AF:

0.0198

Gnomad4 OTH

AF:

0.0535

Alfa

AF:

0.0263

Hom.:

690

Bravo

AF:

0.0718

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0183

AC:

ESP6500AA

AF:

0.113

AC:

434

ESP6500EA

AF:

0.0214

AC:

144

ExAC

AF:

0.0740

AC:

8984

EpiCase

AF:

0.0180

EpiControl

AF:

0.0170

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

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.Ile431Val in exon 11 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 11.3% (434/3833) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs62635003). -

Primary ciliary dyskinesia

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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

0.063

BayesDel_addAF

Benign

-0.99

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.0010

DANN

Benign

0.55

DEOGEN2

Benign

0.036

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

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.53

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

MetaRNN

Benign

0.0019

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

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

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.50

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

REVEL

Benign

0.0050

Sift

Benign

0.25

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

Sift4G

Benign

0.32

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

Polyphen

0.019

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

Vest4

0.036

MPC

0.022

ClinPred

0.0088

GERP RS

-9.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.14

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