rs5918522

Variant names:

• chrX-38298940-T-C
• rs5918522
• NM_001034853.2:c.1245+16A>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.1245+16A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,204,044 control chromosomes in the GnomAD database, including 11,286 homozygotes. There are 59,827 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (911 hom., 4224 hem., cov: 23)
  • Exomes 𝑓: 0.16 (10375 hom. 55603 hem.)
• Consequence: RPGR NM_001034853.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.709
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-38298940-T-C is Benign according to our data. Variant chrX-38298940-T-C is described in ClinVar as Benign. ClinVar VariationId is 98731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.1245+16A>G		intron_variant	Intron 10 of 14	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.1245+16A>G		intron_variant	Intron 10 of 14		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-367181T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 15112 AN: 111513 Hom.: 910 Cov.: 23

Gnomad AFR AF: 0.0903

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.000556

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.165

GnomAD2 exomes AF: 0.123 AC: 22590 AN: 182946 AF XY: 0.125

Gnomad AFR exome AF: 0.0865

Gnomad AMR exome AF: 0.0802

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.172

Gnomad OTH exome AF: 0.164

GnomAD4 exome AF: 0.159 AC: 173275 AN: 1092481 Hom.: 10375 Cov.: 29 AF XY: 0.155 AC XY: 55603 AN XY: 358275

African (AFR) AF: 0.0886 AC: 2332 AN: 26308

American (AMR) AF: 0.0856 AC: 3012 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 4508 AN: 19343

East Asian (EAS) AF: 0.000298 AC: 9 AN: 30183

South Asian (SAS) AF: 0.0432 AC: 2337 AN: 54035

European-Finnish (FIN) AF: 0.122 AC: 4950 AN: 40505

Middle Eastern (MID) AF: 0.214 AC: 877 AN: 4098

European-Non Finnish (NFE) AF: 0.177 AC: 148030 AN: 836892

Other (OTH) AF: 0.157 AC: 7220 AN: 45934

GnomAD4 genome AF: 0.135 AC: 15102 AN: 111563 Hom.: 911 Cov.: 23 AF XY: 0.125 AC XY: 4224 AN XY: 33745

African (AFR) AF: 0.0901 AC: 2774 AN: 30775

American (AMR) AF: 0.126 AC: 1321 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 606 AN: 2640

East Asian (EAS) AF: 0.000558 AC: 2 AN: 3586

South Asian (SAS) AF: 0.0381 AC: 102 AN: 2676

European-Finnish (FIN) AF: 0.110 AC: 658 AN: 5962

Middle Eastern (MID) AF: 0.237 AC: 51 AN: 215

European-Non Finnish (NFE) AF: 0.174 AC: 9235 AN: 53038

Other (OTH) AF: 0.163 AC: 246 AN: 1512

Alfa AF: 0.151 Hom.: 2463

Bravo AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: 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 -

Jan 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.076
DANN	Benign	0.31
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs5918522; hg19: chrX-38158193;