rs4084271

Variant names:

• chrX-38273375-A-G
• rs4084271
• ENST00000465127.1:c.172-392746A>G

Variant summary

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

The ENST00000465127.1(ENSG00000250349):​c.172-392746A>G 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: ENSG00000250349 ENST00000465127.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.42
• Publications: 6 publications found

Genes affected

ENSG00000250349 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 227048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_000328.3	c.2241+11T>C		intron_variant	Intron 18 of 18		NP_000319.1
RPGR	NM_001367245.1	c.2238+11T>C		intron_variant	Intron 18 of 18		NP_001354174.1
RPGR	NM_001367246.1	c.2055+11T>C		intron_variant	Intron 17 of 17		NP_001354175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-392746A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 22374 AN: 111298 Hom.: 1968 Cov.: 23

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

GnomAD2 exomes AF: 0.197 AC: 31928 AN: 161709 AF XY: 0.207

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 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

African (AFR) AF: 0.0981 AC: 2535 AN: 25844

American (AMR) AF: 0.113 AC: 3852 AN: 34083

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 6896 AN: 18980

East Asian (EAS) AF: 0.000567 AC: 17 AN: 29982

South Asian (SAS) AF: 0.211 AC: 11042 AN: 52242

European-Finnish (FIN) AF: 0.204 AC: 8045 AN: 39385

Middle Eastern (MID) AF: 0.385 AC: 1324 AN: 3438

European-Non Finnish (NFE) AF: 0.267 AC: 215880 AN: 809737

Other (OTH) AF: 0.242 AC: 10799 AN: 44708

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

African (AFR) AF: 0.101 AC: 3121 AN: 30797

American (AMR) AF: 0.169 AC: 1775 AN: 10495

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 954 AN: 2641

East Asian (EAS) AF: 0.00112 AC: 4 AN: 3567

South Asian (SAS) AF: 0.200 AC: 533 AN: 2666

European-Finnish (FIN) AF: 0.201 AC: 1185 AN: 5908

Middle Eastern (MID) AF: 0.408 AC: 87 AN: 213

European-Non Finnish (NFE) AF: 0.268 AC: 14146 AN: 52869

Other (OTH) AF: 0.235 AC: 357 AN: 1519

Alfa AF: 0.251 Hom.: 18316

Bravo AF: 0.192

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 3 Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Macular degeneration, X-linked atrophic Benign:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked cone-rod dystrophy 1 Benign:1

Nov 07, 2021

Genome-Nilou Lab

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	-0.57
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		2.4
Mutation Taster		=100/0	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: rs4084271; hg19: chrX-38132628;