rs5917557

chrX-38286658-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.2341G>A(p.Ala781Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,131,478 control chromosomes in the GnomAD database, including 10,907 homozygotes. There are 54,741 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A781V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (785 hom., 1169 hem., cov: 11)
  • Exomes 𝑓: 0.16 (10122 hom. 53572 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.308

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=0.00457561).
• BP6: Variant X-38286658-C-T is Benign according to our data. Variant chrX-38286658-C-T is described in ClinVar as [Benign]. Clinvar id is 257193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38286658-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.2341G>A	p.Ala781Thr	missense_variant	15/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.2341G>A	p.Ala781Thr	missense_variant	15/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 10242 AN: 79301 Hom.: 784 Cov.: 11 AF XY: 0.0989 AC XY: 1170 AN XY: 11831

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.0992

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.122 AC: 13768 AN: 113184 Hom.: 748 AF XY: 0.119 AC XY: 4758 AN XY: 40122

Gnomad AFR exome AF: 0.0862

Gnomad AMR exome AF: 0.0876

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0418

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.160 AC: 168047 AN: 1052147 Hom.: 10122 Cov.: 36 AF XY: 0.156 AC XY: 53572 AN XY: 344163

Gnomad4 AFR exome AF: 0.0877

Gnomad4 AMR exome AF: 0.0916

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.000258

Gnomad4 SAS exome AF: 0.0439

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.129 AC: 10238 AN: 79331 Hom.: 785 Cov.: 11 AF XY: 0.0986 AC XY: 1169 AN XY: 11861

Gnomad4 AFR AF: 0.0815

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0272

Gnomad4 FIN AF: 0.0992

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.144

Alfa AF: 0.168 Hom.: 9629

Bravo AF: 0.135

TwinsUK AF: 0.174 AC: 646

ALSPAC AF: 0.173 AC: 501

ESP6500AA AF: 0.0842 AC: 280

ESP6500EA AF: 0.169 AC: 973

ExAC AF: 0.0834 AC: 3127

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 29, 2016	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 14, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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
BayesDel_addAF	Benign	-1.1	T
BayesDel_noAF	Benign	-1.2
Cadd	Benign	4.7
Dann	Benign	0.80
FATHMM_MKL	Benign	0.013	N
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.20	T
Vest4		0.028
MPC		0.76
ClinPred		0.00093	T
GERP RS		-2.2
gMVP		0.0030

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: rs5917557; hg19: chrX-38145911; COSMIC: COSV58835375;