rs144635565

Variant names:

• chrX-38297331-T-C
• rs144635565
• NM_001034853.2:c.1367A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1 BP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_001034853.2(RPGR):c.1367A>G (p.Gln456Arg) variant is a missense variant encoding the substitution of Glutamine with Arginine at amino acid 456. This variant is present in gnomAD v.4.1.0 at a frequency of 0.01145 among hemizygous individuals, with 4533 variant alleles / 395737 hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in three probands with an alternate molecular basis for the disease (PMIDs: 18552978, 22334370, 11992260). However, the BP5 code is considered not applicable for RPGR-related retinopathy. The computational predictor REVEL gives a score of 0.016, which is below the ClinGen X-linked IRD VCEP threshold of < 0.016 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.08, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_strong). In summary, this variant is classified as benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BA1 and BP4_strong. (VCEP specifications version 1.0.0; date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146033/MONDO:0100437/106

• Frequency:
  • Genomes: 𝑓 0.0079 (2 hom., 224 hem., cov: 22)
  • Exomes 𝑓: 0.012 (71 hom. 4309 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:12
• Conservation: PhyloP100: 0.0240
• Publications: 9 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, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• RPGR-related retinopathy

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

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

Specifications for RPGR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: 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.1367A>G	p.Gln456Arg	missense	Exon 11 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1367A>G	p.Gln456Arg	missense	Exon 11 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1364A>G	p.Gln455Arg	missense	Exon 11 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1367A>G	p.Gln456Arg	missense	Exon 11 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-368790T>C		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000494841.1	TSL:1	n.630A>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.00788 AC: 869 AN: 110303 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00598

Gnomad ASJ AF: 0.000759

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.00943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00473

GnomAD2 exomes AF: 0.00831 AC: 1524 AN: 183345 AF XY: 0.00796

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00248

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.0124 AC: 13585 AN: 1097770 Hom.: 71 Cov.: 30 AF XY: 0.0119 AC XY: 4309 AN XY: 363160

African (AFR) AF: 0.00114 AC: 30 AN: 26394

American (AMR) AF: 0.00256 AC: 90 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 23 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30188

South Asian (SAS) AF: 0.00495 AC: 268 AN: 54140

European-Finnish (FIN) AF: 0.0120 AC: 485 AN: 40523

Middle Eastern (MID) AF: 0.00169 AC: 7 AN: 4131

European-Non Finnish (NFE) AF: 0.0145 AC: 12238 AN: 841742

Other (OTH) AF: 0.00964 AC: 444 AN: 46075

GnomAD4 genome AF: 0.00787 AC: 869 AN: 110357 Hom.: 2 Cov.: 22 AF XY: 0.00688 AC XY: 224 AN XY: 32577

African (AFR) AF: 0.00207 AC: 63 AN: 30430

American (AMR) AF: 0.00598 AC: 61 AN: 10209

Ashkenazi Jewish (ASJ) AF: 0.000759 AC: 2 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3471

South Asian (SAS) AF: 0.00353 AC: 9 AN: 2552

European-Finnish (FIN) AF: 0.00943 AC: 54 AN: 5726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0127 AC: 673 AN: 52932

Other (OTH) AF: 0.00466 AC: 7 AN: 1501

Alfa AF: 0.0108 Hom.: 512

Bravo AF: 0.00682

TwinsUK AF: 0.0159 AC: 59

ALSPAC AF: 0.0163 AC: 47

ESP6500AA AF: 0.00209 AC: 8

ESP6500EA AF: 0.0106 AC: 71

ExAC AF: 0.00889 AC: 1079

EpiCase AF: 0.0118

EpiControl AF: 0.00878

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	2	Primary ciliary dyskinesia (2)
-	1	-	Retinal dystrophy (1)
-	-	1	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.44
DEOGEN2	Benign	0.031	T
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N
PhyloP100		0.024
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.016
Sift	Benign	0.46	T
Sift4G	Benign	0.55	T
Polyphen		0.0030	B
Vest4		0.035
MVP		0.082
MPC		0.022
ClinPred		0.0019	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.11
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs144635565; hg19: chrX-38156584; COSMIC: COSV58835190; COSMIC: COSV58835190;