rs12688514

Variant names:

• chrX-38285569-C-T
• rs12688514
• NM_001034853.2:c.3430G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38285569-C-T
• chrX-38285569-C-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: NM_001034853.2(RPGR):c.3430G>A (p.Val1144Ile) is a missense variant predicted to replace valine with isoleucine at amino acid 1144. This variant is present in gnomAD v.4.1.0 at a frequency of 0.1054 among hemizygous individuals, with 41,850 variant alleles / 397,045 total alleles, which is higher than the ClinGen X-linked IRD VCEP BA1 threshold of >0.00005 (BA1). The computational predictor REVEL gives a score of 0.081, 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 and BP4_moderate. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385143/MONDO:0100437/106

• Frequency:
  • Genomes: 𝑓 0.086 (530 hom., 3031 hem., cov: 22)
  • Exomes 𝑓: 0.10 (5636 hom. 38819 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 1.95
• Publications: 16 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.3430G>A	p.Val1144Ile	missense	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+1525G>A		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+1525G>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.3430G>A	p.Val1144Ile	missense	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-380552C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+1525G>A		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 9602 AN: 111316 Hom.: 529 Cov.: 22

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0808

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0762

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.0949

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0747

GnomAD2 exomes AF: 0.140 AC: 25623 AN: 183049 AF XY: 0.139

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.404

Gnomad FIN exome AF: 0.0958

Gnomad NFE exome AF: 0.0828

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.103 AC: 113119 AN: 1097871 Hom.: 5636 Cov.: 34 AF XY: 0.107 AC XY: 38819 AN XY: 363459

African (AFR) AF: 0.0103 AC: 271 AN: 26396

American (AMR) AF: 0.220 AC: 7746 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.0805 AC: 1561 AN: 19383

East Asian (EAS) AF: 0.412 AC: 12428 AN: 30194

South Asian (SAS) AF: 0.223 AC: 12071 AN: 54141

European-Finnish (FIN) AF: 0.0971 AC: 3930 AN: 40454

Middle Eastern (MID) AF: 0.0425 AC: 176 AN: 4137

European-Non Finnish (NFE) AF: 0.0830 AC: 69869 AN: 841891

Other (OTH) AF: 0.110 AC: 5067 AN: 46082

GnomAD4 genome AF: 0.0862 AC: 9605 AN: 111366 Hom.: 530 Cov.: 22 AF XY: 0.0902 AC XY: 3031 AN XY: 33586

African (AFR) AF: 0.0175 AC: 539 AN: 30725

American (AMR) AF: 0.160 AC: 1683 AN: 10513

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 201 AN: 2639

East Asian (EAS) AF: 0.391 AC: 1362 AN: 3479

South Asian (SAS) AF: 0.251 AC: 659 AN: 2629

European-Finnish (FIN) AF: 0.0949 AC: 563 AN: 5934

Middle Eastern (MID) AF: 0.0230 AC: 5 AN: 217

European-Non Finnish (NFE) AF: 0.0833 AC: 4416 AN: 53031

Other (OTH) AF: 0.0804 AC: 122 AN: 1518

Alfa AF: 0.0881 Hom.: 7292

Bravo AF: 0.0903

TwinsUK AF: 0.0817 AC: 303

ALSPAC AF: 0.0865 AC: 250

ESP6500AA AF: 0.0183 AC: 70

ESP6500EA AF: 0.0865 AC: 582

ExAC AF: 0.138 AC: 16713

EpiCase AF: 0.0712

EpiControl AF: 0.0730

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	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	0.16
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.92
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.081
Sift4G	Pathogenic	0.0	D
Vest4		0.10
MPC		0.63
ClinPred		0.018	T
GERP RS		2.7
gMVP		0.085
Mutation Taster		=65/35	polymorphism

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: rs12688514; hg19: chrX-38144822; COSMIC: COSV58841320;