rs1801687

Positions:

• chrX-38297424-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001034853.2(RPGR):​c.1274G>A​(p.Arg425Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,205,424 control chromosomes in the GnomAD database, including 2,698 homozygotes. There are 26,057 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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.093 (504 hom., 2831 hem., cov: 21)
  • Exomes 𝑓: 0.063 (2194 hom. 23226 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:2
• Conservation: PhyloP100: -0.241

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003427893).
• BP6: Variant X-38297424-C-T is Benign according to our data. Variant chrX-38297424-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 98734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38297424-C-T is described in Lovd as [Benign]. Variant chrX-38297424-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.1274G>A	p.Arg425Lys	missense_variant	11/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.1274G>A	p.Arg425Lys	missense_variant	11/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 10202 AN: 109447 Hom.: 506 Cov.: 21 AF XY: 0.0886 AC XY: 2822 AN XY: 31837

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.0697

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.0603

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0791

GnomAD3 exomes AF: 0.101 AC: 18517 AN: 182620 Hom.: 1026 AF XY: 0.0912 AC XY: 6125 AN XY: 67176

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.0690

Gnomad SAS exome AF: 0.151

Gnomad FIN exome AF: 0.0947

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0746

GnomAD4 exome AF: 0.0633 AC: 69387 AN: 1095925 Hom.: 2194 Cov.: 29 AF XY: 0.0642 AC XY: 23226 AN XY: 361895

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.0609

Gnomad4 EAS exome AF: 0.0781

Gnomad4 SAS exome AF: 0.146

Gnomad4 FIN exome AF: 0.0915

Gnomad4 NFE exome AF: 0.0462

Gnomad4 OTH exome AF: 0.0665

GnomAD4 genome AF: 0.0932 AC: 10210 AN: 109499 Hom.: 504 Cov.: 21 AF XY: 0.0887 AC XY: 2831 AN XY: 31899

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0691

Gnomad4 EAS AF: 0.0699

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0923

Gnomad4 NFE AF: 0.0491

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0591 Hom.: 3055

Bravo AF: 0.104

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0509 AC: 147

ESP6500AA AF: 0.154 AC: 591

ESP6500EA AF: 0.0511 AC: 344

ExAC AF: 0.0972 AC: 11798

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Arg425Lys in exon 11 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 15.4% (591/3833) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1801687). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -

not provided Benign:1 Other:2

not provided, no classification provided	literature only	Retina International	-	- -
not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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	Invitae	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	0.078
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.075
DANN	Benign	0.41
FATHMM_MKL	Benign	0.0073	N
MetaRNN	Benign	0.0034	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;N;.;.;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.15	N;.;N;.;.;.;N
REVEL	Benign	0.0050
Sift	Benign	0.97	T;.;T;.;.;.;.
Sift4G	Benign	0.41	T;.;T;.;.;.;T
Polyphen		0.0	B;B;.;.;.;.;.
Vest4		0.092
MPC		0.021
ClinPred		0.00023	T
GERP RS		-5.9
Varity_R		0.071
gMVP		0.21

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

Other links and lift over

dbSNP: rs1801687; hg19: chrX-38156677; COSMIC: COSV58833750; COSMIC: COSV58833750;