NM_001034853.2:c.1291A>G

Variant names:

• chrX-38297407-T-C
• rs62635003
• NM_001034853.2:c.1291A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001034853.2(RPGR):​c.1291A>G​(p.Ile431Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,206,088 control chromosomes in the GnomAD database, including 1,621 homozygotes. There are 16,241 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene RPGR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.061 (269 hom., 1895 hem., cov: 22)
  • Exomes 𝑓: 0.037 (1352 hom. 14346 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:10 O:1
• Conservation: PhyloP100: -2.15
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001911819).
• BP6: Variant X-38297407-T-C is Benign according to our data. Variant chrX-38297407-T-C is described in ClinVar as Benign. ClinVar VariationId is 98737.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

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.1291A>G	p.Ile431Val	missense	Exon 11 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1291A>G	p.Ile431Val	missense	Exon 11 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1288A>G	p.Ile430Val	missense	Exon 11 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1291A>G	p.Ile431Val	missense	Exon 11 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-368714T>C		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000494841.1	TSL:1	n.554A>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0613 AC: 6730 AN: 109759 Hom.: 270 Cov.: 22

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0247

Gnomad EAS AF: 0.0690

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0543

GnomAD2 exomes AF: 0.0786 AC: 14382 AN: 182938 AF XY: 0.0701

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.216

Gnomad ASJ exome AF: 0.0191

Gnomad EAS exome AF: 0.0696

Gnomad FIN exome AF: 0.0752

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0434

GnomAD4 exome AF: 0.0375 AC: 41071 AN: 1096274 Hom.: 1352 Cov.: 29 AF XY: 0.0396 AC XY: 14346 AN XY: 362000

African (AFR) AF: 0.124 AC: 3272 AN: 26320

American (AMR) AF: 0.202 AC: 7115 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 370 AN: 19364

East Asian (EAS) AF: 0.0784 AC: 2365 AN: 30169

South Asian (SAS) AF: 0.143 AC: 7726 AN: 54038

European-Finnish (FIN) AF: 0.0695 AC: 2816 AN: 40493

Middle Eastern (MID) AF: 0.0248 AC: 102 AN: 4111

European-Non Finnish (NFE) AF: 0.0184 AC: 15454 AN: 840615

Other (OTH) AF: 0.0402 AC: 1851 AN: 46014

GnomAD4 genome AF: 0.0613 AC: 6737 AN: 109814 Hom.: 269 Cov.: 22 AF XY: 0.0590 AC XY: 1895 AN XY: 32110

African (AFR) AF: 0.115 AC: 3463 AN: 30148

American (AMR) AF: 0.106 AC: 1076 AN: 10140

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 65 AN: 2634

East Asian (EAS) AF: 0.0692 AC: 239 AN: 3454

South Asian (SAS) AF: 0.139 AC: 357 AN: 2561

European-Finnish (FIN) AF: 0.0725 AC: 406 AN: 5602

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.0198 AC: 1049 AN: 52883

Other (OTH) AF: 0.0535 AC: 80 AN: 1494

Alfa AF: 0.0339 Hom.: 1060

Bravo AF: 0.0718

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0183 AC: 53

ESP6500AA AF: 0.113 AC: 434

ESP6500EA AF: 0.0214 AC: 144

ExAC AF: 0.0740 AC: 8984

EpiCase AF: 0.0180

EpiControl AF: 0.0170

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	Retinal dystrophy (1)
-	-	1	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.99	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0010
DANN	Benign	0.55
DEOGEN2	Benign	0.036	T
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-2.1
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.0050
Sift	Benign	0.25	T
Sift4G	Benign	0.32	T
Polyphen		0.019	B
Vest4		0.036
MPC		0.022
ClinPred		0.0088	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.14
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: rs62635003; hg19: chrX-38156660; COSMIC: COSV58833722; COSMIC: COSV58833722;