rs5917557

Variant names:

• chrX-38286658-C-T
• rs5917557
• NM_001034853.2:c.2341G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BA1 BS2

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.2341G>A (p.Ala781Thr) is a missense variant encoding the substitution of alanine with threonine at amino acid 781. This variant is present in gnomAD v.4.1.0 at a frequency of 0.1538 among hemizygous individuals, with 54,741 variant alleles / 356,024 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been identified in 13 healthy individuals meeting the BS2 requirement of no electroretinogram defects by the age of 30 years (PMIDs: 12657579, 18552978, 18552978, 32679846, BS2). The computational predictor REVEL gives a score of 0.059, which is below the ClinGen X-linked IRD VCEP threshold of <0.183 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_moderate). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ClinGen X-linked Inherited Retinal Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RPGR Version 1.0.0; BA1, BS2, and BP4_moderate. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385291/MONDO:0100437/106

• 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 reviewed by expert panel B:7
• Conservation: PhyloP100: 0.308
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 3

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• RPGR-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• primary ciliary dyskinesia-retinitis pigmentosa syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macular degeneration, X-linked atrophic

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.2341G>A	p.Ala781Thr	missense	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+436G>A		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+436G>A		intron	N/A	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.2341G>A	p.Ala781Thr	missense	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-379463C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+436G>A		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 10242 AN: 79301 Hom.: 784 Cov.: 11

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

GnomAD2 exomes AF: 0.122 AC: 13768 AN: 113184 AF XY: 0.119

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 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

African (AFR) AF: 0.0877 AC: 2179 AN: 24855

American (AMR) AF: 0.0916 AC: 2557 AN: 27902

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 4345 AN: 18629

East Asian (EAS) AF: 0.000258 AC: 7 AN: 27117

South Asian (SAS) AF: 0.0439 AC: 2185 AN: 49800

European-Finnish (FIN) AF: 0.123 AC: 4604 AN: 37547

Middle Eastern (MID) AF: 0.217 AC: 639 AN: 2947

European-Non Finnish (NFE) AF: 0.176 AC: 144559 AN: 819095

Other (OTH) AF: 0.158 AC: 6972 AN: 44255

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

African (AFR) AF: 0.0815 AC: 1661 AN: 20375

American (AMR) AF: 0.102 AC: 698 AN: 6816

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 436 AN: 2040

East Asian (EAS) AF: 0.000386 AC: 1 AN: 2592

South Asian (SAS) AF: 0.0272 AC: 36 AN: 1325

European-Finnish (FIN) AF: 0.0992 AC: 360 AN: 3630

Middle Eastern (MID) AF: 0.174 AC: 25 AN: 144

European-Non Finnish (NFE) AF: 0.166 AC: 6796 AN: 40867

Other (OTH) AF: 0.144 AC: 153 AN: 1064

Alfa AF: 0.164 Hom.: 10139

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

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Retinal dystrophy (1)
-	-	1	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
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
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.93	T
PhyloP100		0.31
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.059
Sift4G	Benign	0.61	T
Vest4		0.028
MPC		0.76
ClinPred		0.00093	T
GERP RS		-2.2
gMVP		0.0030
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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