rs150960964

Variant names:

• chrX-38285592-C-T
• rs150960964
• NM_001034853.2:c.3407G>A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.3407G>A (p.Gly1136Asp) variant is a missense variant encoding the substitution of glycine with aspartic acid at amino acid 1136. The computational predictor REVEL gives a score of 0.053, 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). This variant is present in gnomAD v.4.1.0 at a frequency of 0.0008861 among hemizygous individuals, with 352 variant alleles / 397,264 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). This variant has been reported in at least 1 male proband and 2 females. The male proband had insufficient reported details and did not meet the PS4 requirement of some functional vision impairment in an affected male by age 30 years, or decreased/absent cone and/or rod electroretinogram responses (PMID:32679846), so PS4_supporting was not met. 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 and BP4_moderate. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385145/MONDO:0100437/106

• Frequency:
  • Genomes: 𝑓 0.0061 (5 hom., 179 hem., cov: 22)
  • Exomes 𝑓: 0.00067 (2 hom. 173 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: 0.516
• Publications: 2 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

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.3407G>A	p.Gly1136Asp	missense	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+1502G>A		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+1502G>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.3407G>A	p.Gly1136Asp	missense	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-380529C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+1502G>A		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.00607 AC: 677 AN: 111517 Hom.: 5 Cov.: 22

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00228

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00602

GnomAD2 exomes AF: 0.00176 AC: 322 AN: 183285 AF XY: 0.00118

Gnomad AFR exome AF: 0.0209

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000668 AC: 734 AN: 1098115 Hom.: 2 Cov.: 34 AF XY: 0.000476 AC XY: 173 AN XY: 363495

African (AFR) AF: 0.0214 AC: 565 AN: 26399

American (AMR) AF: 0.00128 AC: 45 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40492

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4137

European-Non Finnish (NFE) AF: 0.0000523 AC: 44 AN: 842063

Other (OTH) AF: 0.00158 AC: 73 AN: 46093

GnomAD4 genome AF: 0.00607 AC: 677 AN: 111565 Hom.: 5 Cov.: 22 AF XY: 0.00530 AC XY: 179 AN XY: 33769

African (AFR) AF: 0.0208 AC: 638 AN: 30720

American (AMR) AF: 0.00228 AC: 24 AN: 10530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5947

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

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53104

Other (OTH) AF: 0.00595 AC: 9 AN: 1513

Alfa AF: 0.00217 Hom.: 90

Bravo AF: 0.00695

ESP6500AA AF: 0.0217 AC: 83

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00193 AC: 234

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Primary ciliary dyskinesia (1)
-	-	1	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	9.4
DANN	Benign	0.84
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.52
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.053
Sift4G	Benign	0.69	T
Vest4		0.23
MVP		0.20
MPC		1.0
ClinPred		0.0069	T
GERP RS		-0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.083
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: rs150960964; hg19: chrX-38144845;