rs1801687

Variant names:

• chrX-38297424-C-T
• rs1801687
• NM_001034853.2:c.1274G>A

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.1274G>A​(p.Arg425Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.066 in 1,205,424 control chromosomes in the GnomAD database, including 2,698 homozygotes. There are 26,057 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R425G) has been classified as Likely benign. The gene RPGR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.093 (504 hom., 2831 hem., cov: 21)
  • Exomes 𝑓: 0.063 (2194 hom. 23226 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:11 O:2
• Conservation: PhyloP100: -0.241
• Publications: 13 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=0.003427893).
• BP6: Variant X-38297424-C-T is Benign according to our data. Variant chrX-38297424-C-T is described in ClinVar as Benign. ClinVar VariationId is 98734.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 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.1274G>A	p.Arg425Lys	missense	Exon 11 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1274G>A	p.Arg425Lys	missense	Exon 11 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1271G>A	p.Arg424Lys	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.1274G>A	p.Arg425Lys	missense	Exon 11 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-368697C>T		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000494841.1	TSL:1	n.537G>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 10202 AN: 109447 Hom.: 506 Cov.: 21

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.0697

Gnomad SAS AF: 0.142

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.0603

Gnomad NFE AF: 0.0491

Gnomad OTH AF: 0.0791

GnomAD2 exomes AF: 0.101 AC: 18517 AN: 182620 AF XY: 0.0912

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.0690

Gnomad FIN exome AF: 0.0947

Gnomad NFE exome AF: 0.0473

Gnomad OTH exome AF: 0.0746

GnomAD4 exome AF: 0.0633 AC: 69387 AN: 1095925 Hom.: 2194 Cov.: 29 AF XY: 0.0642 AC XY: 23226 AN XY: 361895

African (AFR) AF: 0.168 AC: 4426 AN: 26301

American (AMR) AF: 0.219 AC: 7695 AN: 35136

Ashkenazi Jewish (ASJ) AF: 0.0609 AC: 1179 AN: 19363

East Asian (EAS) AF: 0.0781 AC: 2354 AN: 30148

South Asian (SAS) AF: 0.146 AC: 7888 AN: 53974

European-Finnish (FIN) AF: 0.0915 AC: 3702 AN: 40478

Middle Eastern (MID) AF: 0.0699 AC: 286 AN: 4093

European-Non Finnish (NFE) AF: 0.0462 AC: 38800 AN: 840429

Other (OTH) AF: 0.0665 AC: 3057 AN: 46003

GnomAD4 genome AF: 0.0932 AC: 10210 AN: 109499 Hom.: 504 Cov.: 21 AF XY: 0.0887 AC XY: 2831 AN XY: 31899

African (AFR) AF: 0.158 AC: 4745 AN: 30003

American (AMR) AF: 0.128 AC: 1302 AN: 10140

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 182 AN: 2632

East Asian (EAS) AF: 0.0699 AC: 242 AN: 3461

South Asian (SAS) AF: 0.143 AC: 365 AN: 2556

European-Finnish (FIN) AF: 0.0923 AC: 513 AN: 5556

Middle Eastern (MID) AF: 0.0569 AC: 12 AN: 211

European-Non Finnish (NFE) AF: 0.0491 AC: 2594 AN: 52783

Other (OTH) AF: 0.0781 AC: 116 AN: 1485

Alfa AF: 0.0653 Hom.: 3702

Bravo AF: 0.104

TwinsUK AF: 0.0472 AC: 175

ALSPAC AF: 0.0509 AC: 147

ESP6500AA AF: 0.154 AC: 591

ESP6500EA AF: 0.0511 AC: 344

ExAC AF: 0.0972 AC: 11798

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (4)
-	-	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	0.078
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.075
DANN	Benign	0.41
DEOGEN2	Benign	0.019	T
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.043	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.24
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.0050
Sift	Benign	0.97	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.092
MPC		0.021
ClinPred		0.00023	T
GERP RS		-5.9
Varity_R		0.071
gMVP		0.21
Mutation Taster		=94/6	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: rs1801687; hg19: chrX-38156677; COSMIC: COSV58833750; COSMIC: COSV58833750;