rs41305223

Positions:

chrX-38301273-T-C

Variant summary

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

The NM_001034853.2(RPGR):c.1033A>G(p.Asn345Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,203,141 control chromosomes in the GnomAD database, including 51 homozygotes. There are 3,751 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 0.0071 ( 2 hom., 204 hem., cov: 22)

Exomes 𝑓: 0.010 ( 49 hom. 3547 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: 0.789

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=0.0090559125).

BP6

Variant X-38301273-T-C is Benign according to our data. Variant chrX-38301273-T-C is described in ClinVar as [Benign]. Clinvar id is 98725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38301273-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00709 (790/111478) while in subpopulation NFE AF= 0.0117 (622/53079). AF 95% confidence interval is 0.011. There are 2 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2 linkuse as main transcript	c.1033A>G	p.Asn345Asp	missense_variant	9/15	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.1033A>G	p.Asn345Asp	missense_variant	9/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-364848T>C		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00710

AC:

791

AN:

111428

Hom.:

Cov.:

AF XY:

0.00609

AC XY:

205

AN XY:

33658

show subpopulations

Gnomad AFR

AF:

0.00229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00325

Gnomad ASJ

AF:

0.00228

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00150

Gnomad FIN

AF:

0.00754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.00667

GnomAD3 exomes

AF:

0.00706

AC:

1268

AN:

179715

Hom.:

AF XY:

0.00660

AC XY:

426

AN XY:

64497

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00270

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00702

Gnomad NFE exome

AF:

0.0120

Gnomad OTH exome

AF:

0.00920

GnomAD4 exome

AF:

0.0104

AC:

11320

AN:

1091663

Hom.:

Cov.:

AF XY:

0.00992

AC XY:

3547

AN XY:

357487

show subpopulations

Gnomad4 AFR exome

AF:

0.000875

Gnomad4 AMR exome

AF:

0.00310

Gnomad4 ASJ exome

AF:

0.00290

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00195

Gnomad4 FIN exome

AF:

0.00742

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00822

GnomAD4 genome

AF:

0.00709

AC:

790

AN:

111478

Hom.:

Cov.:

AF XY:

0.00605

AC XY:

204

AN XY:

33718

show subpopulations

Gnomad4 AFR

AF:

0.00225

Gnomad4 AMR

AF:

0.00325

Gnomad4 ASJ

AF:

0.00228

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00151

Gnomad4 FIN

AF:

0.00754

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.00658

Alfa

AF:

0.0104

Hom.:

483

Bravo

AF:

0.00635

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00313

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00760

AC:

922

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2018	This variant is associated with the following publications: (PMID: 10937588, 11857109) -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 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	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.63

CADD

Benign

4.7

DANN

Benign

0.89

DEOGEN2

Uncertain

0.43

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

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.67

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

MetaRNN

Benign

0.0091

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

MetaSVM

Benign

-0.79

MutationAssessor

Benign

1.2

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

PrimateAI

Benign

0.27

PROVEAN

Benign

-2.3

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

REVEL

Benign

0.24

Sift

Benign

0.34

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

Sift4G

Benign

0.40

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

Polyphen

0.020

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

Vest4

0.12

MVP

0.64

MPC

1.1

ClinPred

0.013

GERP RS

-3.1

Varity_R

0.25

gMVP

0.76

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