rs62636730

Variant names:

• chrX-38285768-A-T
• rs62636730
• NM_001034853.2:c.3231T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BA1 BS2_Supporting BP4_Strong

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.3231T>A (p.Asn1077Lys) is a missense variant encoding the substitution of asparagine with lysine at position 1077. This variant is present in gnomAD v.4.1.0 at a frequency of 0.02339 among hemizygous individuals, with 9,240 variant alleles / 395,050 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 0.05, 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 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_strong). This variant has been reported in at least 2 apparently unrelated control individuals meeting the BS2 requirement of no functional visual impairment by age 30 years (PMIDs: 12657579, BS2_supporting). 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, BP4_strong, and BS2_supporting. (date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385168/MONDO:0100437/106

• Frequency:
  • Genomes: 𝑓 0.020 (38 hom., 597 hem., cov: 21)
  • Exomes 𝑓: 0.025 (250 hom. 8643 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:6
• Conservation: PhyloP100: -0.807
• Publications: 5 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 -13 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.3231T>A	p.Asn1077Lys	missense_variant	Exon 15 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.3231T>A	p.Asn1077Lys	missense_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-380353A>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 2201 AN: 108960 Hom.: 38 Cov.: 21

Gnomad AFR AF: 0.00369

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00162

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0386

Gnomad NFE AF: 0.0291

Gnomad OTH AF: 0.0156

GnomAD2 exomes AF: 0.0193 AC: 3507 AN: 182026 AF XY: 0.0194

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.0443

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0292

GnomAD4 exome AF: 0.0245 AC: 26913 AN: 1098054 Hom.: 250 Cov.: 34 AF XY: 0.0238 AC XY: 8643 AN XY: 363452

African (AFR) AF: 0.00394 AC: 104 AN: 26395

American (AMR) AF: 0.0132 AC: 464 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 810 AN: 19383

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.00345 AC: 187 AN: 54141

European-Finnish (FIN) AF: 0.0214 AC: 867 AN: 40459

Middle Eastern (MID) AF: 0.0406 AC: 168 AN: 4137

European-Non Finnish (NFE) AF: 0.0276 AC: 23241 AN: 842042

Other (OTH) AF: 0.0232 AC: 1071 AN: 46089

GnomAD4 genome AF: 0.0202 AC: 2201 AN: 109016 Hom.: 38 Cov.: 21 AF XY: 0.0189 AC XY: 597 AN XY: 31598

African (AFR) AF: 0.00368 AC: 110 AN: 29880

American (AMR) AF: 0.0165 AC: 169 AN: 10238

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 111 AN: 2617

East Asian (EAS) AF: 0.00 AC: 0 AN: 3438

South Asian (SAS) AF: 0.00163 AC: 4 AN: 2459

European-Finnish (FIN) AF: 0.0194 AC: 110 AN: 5669

Middle Eastern (MID) AF: 0.0376 AC: 8 AN: 213

European-Non Finnish (NFE) AF: 0.0291 AC: 1525 AN: 52342

Other (OTH) AF: 0.0155 AC: 23 AN: 1488

Alfa AF: 0.0278 Hom.: 223

Bravo AF: 0.0190

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0322 AC: 93

ESP6500AA AF: 0.00287 AC: 11

ESP6500EA AF: 0.0293 AC: 197

ExAC AF: 0.0196 AC: 2384

EpiCase AF: 0.0282

EpiControl AF: 0.0289

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:3

Nov 27, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RPGR-related retinopathy Benign:1

May 20, 2025

ClinGen X-linked Inherited Retinal Disease Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_001034853.2(RPGR):c.3231T>A (p.Asn1077Lys) is a missense variant encoding the substitution of asparagine with lysine at position 1077. This variant is present in gnomAD v.4.1.0 at a frequency of 0.02339 among hemizygous individuals, with 9,240 variant alleles / 395,050 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 0.05, 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 0.00, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4_strong). This variant has been reported in at least 2 apparently unrelated control individuals meeting the BS2 requirement of no functional visual impairment by age 30 years (PMIDs: 12657579, BS2_supporting). 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, BP4_strong, and BS2_supporting. (date of approval 05/16/2025). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.99	T
BayesDel_noAF	Benign	-1.2
CADD	Benign	11
DANN	Benign	0.94
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.28	.;T
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.81
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.81	.;N
REVEL	Benign	0.050
Sift4G	Benign	0.67	.;T
Vest4		0.031
MutPred		0.39		Gain of methylation at N1077 (P = 0.005);Gain of methylation at N1077 (P = 0.005);
MPC		0.90
ClinPred		0.0062	T
GERP RS		1.6
gMVP		0.015
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: rs62636730; hg19: chrX-38145021;