rs1801688

Variant names:

• chrX-38287917-C-T
• rs1801688
• NM_001034853.2:c.1697G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The NM_001034853.2(RPGR):c.1697G>A (p.Gly566Glu) variant is a missense variant encoding the substitution of Glycine with Glutamic acid at amino acid 566. This variant is present in gnomAD v.4.1.0 at a frequency of 0.06732 among hemizygous individuals, with 26691 variant alleles / 396470 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant was shown to have normal protein function and localization (PMID:30622176). The computational predictor REVEL gives a score of 0.063, 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 0.05, 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 likely 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 and BP4_moderate (date of approval 05/15/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA146040/MONDO:0100437/106

• 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 reviewed by expert panel B:11 O:1
• Conservation: PhyloP100: -0.0420
• Publications: 14 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 -9 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.1697G>A	p.Gly566Glu	missense	Exon 14 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1697G>A	p.Gly566Glu	missense	Exon 14 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1694G>A	p.Gly565Glu	missense	Exon 14 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1697G>A	p.Gly566Glu	missense	Exon 14 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-378204C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.1697G>A	p.Gly566Glu	missense	Exon 14 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.0956 AC: 10649 AN: 111340 Hom.: 527 Cov.: 23

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

GnomAD2 exomes AF: 0.102 AC: 18602 AN: 182454 AF XY: 0.0921

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 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

African (AFR) AF: 0.175 AC: 4604 AN: 26367

American (AMR) AF: 0.220 AC: 7726 AN: 35154

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1176 AN: 19354

East Asian (EAS) AF: 0.0784 AC: 2367 AN: 30197

South Asian (SAS) AF: 0.147 AC: 7939 AN: 53985

European-Finnish (FIN) AF: 0.0913 AC: 3694 AN: 40480

Middle Eastern (MID) AF: 0.0666 AC: 275 AN: 4131

European-Non Finnish (NFE) AF: 0.0462 AC: 38897 AN: 841644

Other (OTH) AF: 0.0669 AC: 3084 AN: 46071

GnomAD4 genome AF: 0.0957 AC: 10655 AN: 111393 Hom.: 525 Cov.: 23 AF XY: 0.0942 AC XY: 3170 AN XY: 33643

African (AFR) AF: 0.165 AC: 5037 AN: 30616

American (AMR) AF: 0.130 AC: 1368 AN: 10501

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 182 AN: 2634

East Asian (EAS) AF: 0.0730 AC: 260 AN: 3562

South Asian (SAS) AF: 0.144 AC: 382 AN: 2645

European-Finnish (FIN) AF: 0.0944 AC: 557 AN: 5898

Middle Eastern (MID) AF: 0.0509 AC: 11 AN: 216

European-Non Finnish (NFE) AF: 0.0490 AC: 2605 AN: 53123

Other (OTH) AF: 0.0730 AC: 111 AN: 1520

Alfa AF: 0.0637 Hom.: 4290

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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (3)
-	-	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	0.12
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Benign	0.74
DEOGEN2	Benign	0.045	T
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.042
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.063
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.22
MPC		0.13
ClinPred		0.028	T
GERP RS		0.80
Varity_R		0.091
gMVP		0.075
Mutation Taster		=100/0	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: rs1801688; hg19: chrX-38147170; COSMIC: COSV58832989;