rs4084271

chrX-38273375-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000339363.7(RPGR):c.2856+11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,169,750 control chromosomes in the GnomAD database, including 25,733 homozygotes. There are 88,469 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (1968 hom., 6438 hem., cov: 23)
  • Exomes 𝑓: 0.25 (23765 hom. 82031 hem.)
• Consequence: RPGR ENST00000339363.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.42

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=-0.57).
• BP6: Variant X-38273375-A-G is Benign according to our data. Variant chrX-38273375-A-G is described in ClinVar as [Benign]. Clinvar id is 227048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38273375-A-G is described in Lovd as [Likely_benign]. Variant chrX-38273375-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_000328.3	c.2241+11T>C		intron_variant
RPGR	NM_001367245.1	c.2238+11T>C		intron_variant
RPGR	NM_001367246.1	c.2055+11T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000339363.7	c.2856+11T>C		intron_variant		5		P4
RPGR	ENST00000642395.2	c.2241+11T>C		intron_variant				A2
RPGR	ENST00000644238.1	c.1722+11T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.201 AC: 22374 AN: 111298 Hom.: 1968 Cov.: 23 AF XY: 0.192 AC XY: 6438 AN XY: 33510

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.294

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.412

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.239

GnomAD3 exomes AF: 0.197 AC: 31928 AN: 161709 Hom.: 2591 AF XY: 0.207 AC XY: 10734 AN XY: 51941

Gnomad AFR exome AF: 0.0942

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.360

Gnomad EAS exome AF: 0.000464

Gnomad SAS exome AF: 0.205

Gnomad FIN exome AF: 0.198

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.246 AC: 260390 AN: 1058399 Hom.: 23765 Cov.: 23 AF XY: 0.245 AC XY: 82031 AN XY: 334153

Gnomad4 AFR exome AF: 0.0981

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.363

Gnomad4 EAS exome AF: 0.000567

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.204

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.242

GnomAD4 genome AF: 0.201 AC: 22361 AN: 111351 Hom.: 1968 Cov.: 23 AF XY: 0.192 AC XY: 6438 AN XY: 33573

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.00112

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.201

Gnomad4 NFE AF: 0.268

Gnomad4 OTH AF: 0.235

Alfa AF: 0.259 Hom.: 14651

Bravo AF: 0.192

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	2241+11T>C in intron 18A of RPGR: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 28.8% (1940/6727) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs4084271). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Retinitis pigmentosa 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Macular degeneration, X-linked atrophic Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

X-linked cone-rod dystrophy 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	14
Dann	Benign	0.83

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

Publications

LitVar

Other links and lift over

dbSNP: rs4084271; hg19: chrX-38132628;