rs1801688

chrX-38287917-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.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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.0420

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=0.0034307837).
• 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	UniProt
RPGR	NM_001034853.2	c.1697G>A	p.Gly566Glu	missense_variant	14/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.1697G>A	p.Gly566Glu	missense_variant	14/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.0956 AC: 10649 AN: 111340 Hom.: 527 Cov.: 23 AF XY: 0.0942 AC XY: 3163 AN XY: 33578

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

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.: 31 AF XY: 0.0648 AC XY: 23521 AN XY: 362827

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.: 23 AF XY: 0.0942 AC XY: 3170 AN XY: 33643

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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.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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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. -

not provided Benign:1 Other:1

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

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	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	11
Dann	Benign	0.74
FATHMM_MKL	Benign	0.023	N
MetaRNN	Benign	0.0034	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;.;L;L
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs1801688; hg19: chrX-38147170; COSMIC: COSV58832989;