rs41312104

chrX-38288016-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034853.2(RPGR):c.1598C>T(p.Thr533Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,207,527 control chromosomes in the GnomAD database, including 288 homozygotes. There are 8,907 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T533A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (38 hom., 621 hem., cov: 22)
  • Exomes 𝑓: 0.024 (250 hom. 8286 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.0500

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 (MetaRNN=0.0017929971).
• BP6: Variant X-38288016-G-A is Benign according to our data. Variant chrX-38288016-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38288016-G-A is described in Lovd as [Likely_benign]. Variant chrX-38288016-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0199 (2225/111643) while in subpopulation NFE AF= 0.029 (1540/53134). AF 95% confidence interval is 0.0278. There are 38 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.1598C>T	p.Thr533Met	missense_variant	14/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.1598C>T	p.Thr533Met	missense_variant	14/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 2225 AN: 111591 Hom.: 38 Cov.: 22 AF XY: 0.0183 AC XY: 620 AN XY: 33833

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0439

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0189 AC: 3446 AN: 182733 Hom.: 31 AF XY: 0.0182 AC XY: 1227 AN XY: 67421

Gnomad AFR exome AF: 0.00411

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.00310

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0238 AC: 26108 AN: 1095884 Hom.: 250 Cov.: 30 AF XY: 0.0229 AC XY: 8286 AN XY: 362224

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0410

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00346

Gnomad4 FIN exome AF: 0.0214

Gnomad4 NFE exome AF: 0.0268

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0199 AC: 2225 AN: 111643 Hom.: 38 Cov.: 22 AF XY: 0.0183 AC XY: 621 AN XY: 33895

Gnomad4 AFR AF: 0.00364

Gnomad4 AMR AF: 0.0160

Gnomad4 ASJ AF: 0.0439

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00150

Gnomad4 FIN AF: 0.0192

Gnomad4 NFE AF: 0.0290

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0278 Hom.: 1219

Bravo AF: 0.0190

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0322 AC: 93

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.0293 AC: 197

ExAC AF: 0.0195 AC: 2362

EpiCase AF: 0.0281

EpiControl AF: 0.0287

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Thr533Met in exon 14 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 2.9% (197/6728) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs41312104). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
not provided, no classification provided	literature only	Retina International	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.015
Dann	Benign	0.78
FATHMM_MKL	Benign	0.0036	N
MetaRNN	Benign	0.0018	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.79	N;N;N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N;.;N;.;.;N
REVEL	Benign	0.015
Sift	Benign	0.16	T;.;T;.;.;.
Sift4G	Benign	0.14	T;.;T;.;.;T
Polyphen		0.27	B;B;.;.;.;.
Vest4		0.061
MPC		0.022
ClinPred		0.0098	T
GERP RS		-3.7
Varity_R		0.012
gMVP		0.061

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: rs41312104; hg19: chrX-38147269;