rs111631988

Positions:

• chrX-38322877-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001034853.2(RPGR):​c.223A>G​(p.Ile75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,208,675 control chromosomes in the GnomAD database, including 224 homozygotes. There are 5,304 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.032 (85 hom., 1018 hem., cov: 23)
  • Exomes 𝑓: 0.012 (139 hom. 4286 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 0.0920

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 -18 ACMG points.

• PM1: In a repeat RCC1 1 (size 51) in uniprot entity RPGR_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_001034853.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0020298362).
• BP6: Variant X-38322877-T-C is Benign according to our data. Variant chrX-38322877-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 100560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38322877-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0856 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.223A>G	p.Ile75Val	missense_variant	3/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.223A>G	p.Ile75Val	missense_variant	3/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.0315 AC: 3538 AN: 112158 Hom.: 84 Cov.: 23 AF XY: 0.0294 AC XY: 1010 AN XY: 34312

Gnomad AFR AF: 0.0882

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.00148

Gnomad MID AF: 0.0385

Gnomad NFE AF: 0.00930

Gnomad OTH AF: 0.0217

GnomAD3 exomes AF: 0.0159 AC: 2909 AN: 183460 Hom.: 52 AF XY: 0.0147 AC XY: 998 AN XY: 67914

Gnomad AFR exome AF: 0.0958

Gnomad AMR exome AF: 0.00769

Gnomad ASJ exome AF: 0.0210

Gnomad EAS exome AF: 0.00649

Gnomad SAS exome AF: 0.0167

Gnomad FIN exome AF: 0.00175

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0121 AC: 13283 AN: 1096466 Hom.: 139 Cov.: 28 AF XY: 0.0118 AC XY: 4286 AN XY: 362086

Gnomad4 AFR exome AF: 0.0903

Gnomad4 AMR exome AF: 0.00861

Gnomad4 ASJ exome AF: 0.0193

Gnomad4 EAS exome AF: 0.00252

Gnomad4 SAS exome AF: 0.0140

Gnomad4 FIN exome AF: 0.00222

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.0149

GnomAD4 genome AF: 0.0316 AC: 3548 AN: 112209 Hom.: 85 Cov.: 23 AF XY: 0.0296 AC XY: 1018 AN XY: 34373

Gnomad4 AFR AF: 0.0884

Gnomad4 AMR AF: 0.0164

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.00445

Gnomad4 SAS AF: 0.0109

Gnomad4 FIN AF: 0.00148

Gnomad4 NFE AF: 0.00930

Gnomad4 OTH AF: 0.0221

Alfa AF: 0.0126 Hom.: 542

Bravo AF: 0.0357

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00692 AC: 20

ESP6500AA AF: 0.0895 AC: 343

ESP6500EA AF: 0.00907 AC: 61

ExAC AF: 0.0168 AC: 2044

EpiCase AF: 0.0106

EpiControl AF: 0.0112

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 22995991, 22025579, 9399904, 27884173) -
Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 27, 2019	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Ile75Val in exon 3 of RPGR: This variant is not expected to have clinical sign ificance because it has been identified in 8.9% (343/3833) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs111631988). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2022	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

X-linked cone-rod dystrophy 1;C1845667:Retinitis pigmentosa 3;C2749137:Retinitis pigmentosa, X-linked, and sinorespiratory infections, with or without deafness;C3151784:Macular degeneration, X-linked atrophic Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.0090
DANN	Benign	0.62
FATHMM_MKL	Benign	0.0049	N
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.93	N;N;N;.;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.51	N;.;N;.;.;.;N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;.;T;.;.;.;.;.
Sift4G	Benign	1.0	T;.;T;.;.;.;T;.
Polyphen		0.0	B;B;.;.;.;.;.;.
Vest4		0.048
MPC		0.60
ClinPred		0.0064	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.066
gMVP		0.78

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: rs111631988; hg19: chrX-38182130;