X-38304704-T-C

Variant names:

• chrX-38304704-T-C
• rs62640587
• NM_001034853.2:c.865A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. BA1 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.865A>G (p.Ile289Val) is a missense variant predicted to cause substitution of isoleucine by valine at amino acid 289. This variant is present in gnomAD v.4.1.0 at a frequency of 0.0001308 among hemizygous individuals, with 51 variant alleles / 389,832 total hemizygous alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The variant co-segregates with X-linked retinitis pigmentosa or milder phenotypes in female carriers across 5 meioses in a single family, however, the description of phenotypes is insufficiently detailed to meet PP4 or PP1 (PMID:10482958). This variant has been reported in at least 2 apparently unrelated probands meeting one of the PS4 requirements of a male with some functional vision impairment by age 30 and/or decreased or absent ERG responses, or a female with functional visual abnormality and documentation of a male relative affected with retinitis pigmentosa (PMIDs: 32531858, 28863407). However, because the variant meets BA1, PS4_Supporting cannot be met. The variant protein exhibits decreased interaction with RPGRIP1 in a yeast-2-hybrid assay (PMID:23213406, PS3_Supporting). The computational predictor REVEL gives the variant a score of 0.553, which is above the ClinGen X-linked IRD VCEP BP4 threshold of <0.290 and below the PP3 threshold of >0.644, so BP4 and PP3 are not met. The computational splicing predictor SpliceAI gives the variant a delta score of 0.01 for acceptor gain, which is below the ClinGen X-linked IRD VCEP BP4 threshold of <0.2 and indicates that the variant has no predicted impact on splicing. In summary, this variant meets the criteria to be 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 and PS3_Supporting. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA226452/MONDO:0100437/106

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (1 hom. 44 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:4 O:1
• Conservation: PhyloP100: 0.0550
• Publications: 3 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)
• 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 -7 ACMG points.

• PS3: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.865A>G	p.Ile289Val	missense	Exon 8 of 15	NP_001030025.1
	RPGR	NM_000328.3		c.865A>G	p.Ile289Val	missense	Exon 8 of 19	NP_000319.1
	RPGR	NM_001367245.1		c.862A>G	p.Ile288Val	missense	Exon 8 of 19	NP_001354174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.865A>G	p.Ile289Val	missense	Exon 8 of 15	ENSP00000495537.1
	RPGR	ENST00000494841.1	TSL:1	n.128A>G		non_coding_transcript_exon	Exon 1 of 4
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-361417T>C		intron	N/A	ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0000983 AC: 11 AN: 111869 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.000150

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 25 AN: 181885 AF XY: 0.000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000260

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000124 AC: 135 AN: 1089955 Hom.: 1 Cov.: 28 AF XY: 0.000124 AC XY: 44 AN XY: 355755

African (AFR) AF: 0.00 AC: 0 AN: 26253

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.000569 AC: 11 AN: 19336

East Asian (EAS) AF: 0.00 AC: 0 AN: 30134

South Asian (SAS) AF: 0.00 AC: 0 AN: 53894

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40501

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4116

European-Non Finnish (NFE) AF: 0.000128 AC: 107 AN: 834715

Other (OTH) AF: 0.000218 AC: 10 AN: 45812

GnomAD4 genome AF: 0.0000983 AC: 11 AN: 111923 Hom.: 0 Cov.: 23 AF XY: 0.000205 AC XY: 7 AN XY: 34077

African (AFR) AF: 0.00 AC: 0 AN: 30844

American (AMR) AF: 0.00 AC: 0 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5998

Middle Eastern (MID) AF: 0.00917 AC: 2 AN: 218

European-Non Finnish (NFE) AF: 0.000150 AC: 8 AN: 53244

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.000244 Hom.: 14

Bravo AF: 0.000132

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000157 AC: 19

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	RPGR-related disorder (1)
-	-	1	RPGR-related retinopathy (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.0060
DANN	Benign	0.65
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-1.3	N
PhyloP100		0.055
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.29	N
REVEL	Uncertain	0.55
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.027	B
Vest4		0.23
MVP		0.81
MPC		0.74
ClinPred		0.039	T
GERP RS		-2.8
PromoterAI		0.010	Neutral
Varity_R		0.055
gMVP		0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62640587; hg19: chrX-38163957;