X-38299102-G-C

Variant names:

• chrX-38299102-G-C
• rs769641256
• NM_001034853.2:c.1099C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS1

This summary comes from the ClinGen Evidence Repository: NM_001034853.2(RPGR):c.1099C>G (p.Pro367Ala) is a missense variant predicted to cause the substitution of proline by alanine at amino acid 367. This variant is present in gnomAD v.4.1.0 at a frequency of 0.00004278 among hemizygous individuals, with 17 variant alleles / 397,359 total alleles, which is higher than the ClinGen X-linked IRD VCEP BS1 threshold of >0.000005 (BS1). The computational predictor REVEL gives a score of 0.285, which is below the ClinGen X-linked IRD VCEP threshold of < 0.290 and predicts a non-damaging effect on RPGR function. Additionally, the splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen X-linked IRD VCEP recommended threshold of <0.1 and does not strongly predict an impact on splicing (BP4). In summary, this variant is classified as likely benign for RPGR-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen X-linked IRD VCEP: BS1, BP4. (VCEP specifications version 1.0.0; date of approval 05/16/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10385542/MONDO:0100437/106

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000036 (0 hom. 15 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:3
• Conservation: PhyloP100: 6.72
• 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)
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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.1099C>G	p.Pro367Ala	missense	Exon 10 of 15	NP_001030025.1
	RPGR	NM_000328.3		c.1099C>G	p.Pro367Ala	missense	Exon 10 of 19	NP_000319.1
	RPGR	NM_001367245.1		c.1096C>G	p.Pro366Ala	missense	Exon 10 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1099C>G	p.Pro367Ala	missense	Exon 10 of 15	ENSP00000495537.1
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-367019G>C		intron	N/A	ENSP00000417050.1
	RPGR	ENST00000494841.1	TSL:1	n.362C>G		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111979 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000769 AC: 14 AN: 182000 AF XY: 0.0000901

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 40 AN: 1097816 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 15 AN XY: 363214

African (AFR) AF: 0.00 AC: 0 AN: 26398

American (AMR) AF: 0.00 AC: 0 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19375

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.00 AC: 0 AN: 54068

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000404 AC: 34 AN: 841908

Other (OTH) AF: 0.0000868 AC: 4 AN: 46076

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111979 Hom.: 0 Cov.: 23 AF XY: 0.0000586 AC XY: 2 AN XY: 34145

African (AFR) AF: 0.00 AC: 0 AN: 30827

American (AMR) AF: 0.00 AC: 0 AN: 10491

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3603

South Asian (SAS) AF: 0.00 AC: 0 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6037

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53244

Other (OTH) AF: 0.00 AC: 0 AN: 1494

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)
-	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	-0.27	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.7
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.28
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.84	P
Vest4		0.62
MutPred		0.48		Gain of catalytic residue at P367 (P = 0.0137)
MVP		0.40
MPC		0.17
ClinPred		0.52	D
GERP RS		4.3
Varity_R		0.85
gMVP		0.80
Mutation Taster		=59/41	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: rs769641256; hg19: chrX-38158355;