rs5918522

Positions:

• chrX-38298940-T-C

Variant summary

Our verdict is Benign. Variant got -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:5 O:1
• Conservation: PhyloP100: -0.709

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 98731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38298940-T-C is described in Lovd as [Likely_benign]. Variant chrX-38298940-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
RPGR	NM_001034853.2	c.1245+16A>G		intron_variant		ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.1245+16A>G		intron_variant			NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.136 AC: 15112 AN: 111513 Hom.: 910 Cov.: 23 AF XY: 0.126 AC XY: 4228 AN XY: 33685

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

GnomAD3 exomes AF: 0.123 AC: 22590 AN: 182946 Hom.: 1163 AF XY: 0.125 AC XY: 8417 AN XY: 67466

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 SAS exome AF: 0.0405

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

Gnomad4 AFR exome AF: 0.0886

Gnomad4 AMR exome AF: 0.0856

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.000298

Gnomad4 SAS exome AF: 0.0432

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.157

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

Gnomad4 AFR AF: 0.0901

Gnomad4 AMR AF: 0.126

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.000558

Gnomad4 SAS AF: 0.0381

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.163

Alfa AF: 0.164 Hom.: 1448

Bravo AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Other:1

not provided, no classification provided

literature only

Retina International

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.076
DANN	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs5918522; hg19: chrX-38158193;