chrX-38285569-C-T

Position:

• chrX-38285569-C-T

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.3430G>A​(p.Val1144Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,209,237 control chromosomes in the GnomAD database, including 6,166 homozygotes. There are 41,850 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (530 hom., 3031 hem., cov: 22)
  • Exomes 𝑓: 0.10 (5636 hom. 38819 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.95

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=0.0035799146).
• BP6: Variant X-38285569-C-T is Benign according to our data. Variant chrX-38285569-C-T is described in ClinVar as [Benign]. Clinvar id is 403388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38285569-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.3430G>A	p.Val1144Ile	missense_variant	15/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.3430G>A	p.Val1144Ile	missense_variant	15/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.0863 AC: 9602 AN: 111316 Hom.: 529 Cov.: 22 AF XY: 0.0903 AC XY: 3029 AN XY: 33526

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0808

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.0762

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.0949

Gnomad MID AF: 0.0210

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0747

GnomAD3 exomes AF: 0.140 AC: 25623 AN: 183049 Hom.: 1863 AF XY: 0.139 AC XY: 9410 AN XY: 67631

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.223

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.404

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.0958

Gnomad NFE exome AF: 0.0828

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.103 AC: 113119 AN: 1097871 Hom.: 5636 Cov.: 34 AF XY: 0.107 AC XY: 38819 AN XY: 363459

Gnomad4 AFR exome AF: 0.0103

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.0805

Gnomad4 EAS exome AF: 0.412

Gnomad4 SAS exome AF: 0.223

Gnomad4 FIN exome AF: 0.0971

Gnomad4 NFE exome AF: 0.0830

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.0862 AC: 9605 AN: 111366 Hom.: 530 Cov.: 22 AF XY: 0.0902 AC XY: 3031 AN XY: 33586

Gnomad4 AFR AF: 0.0175

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.0762

Gnomad4 EAS AF: 0.391

Gnomad4 SAS AF: 0.251

Gnomad4 FIN AF: 0.0949

Gnomad4 NFE AF: 0.0833

Gnomad4 OTH AF: 0.0804

Alfa AF: 0.0921 Hom.: 6105

Bravo AF: 0.0903

TwinsUK AF: 0.0817 AC: 303

ALSPAC AF: 0.0865 AC: 250

ESP6500AA AF: 0.0183 AC: 70

ESP6500EA AF: 0.0865 AC: 582

ExAC AF: 0.138 AC: 16713

EpiCase AF: 0.0712

EpiControl AF: 0.0730

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 27, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 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: MAF -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.92
FATHMM_MKL	Benign	0.67	D
MetaRNN	Benign	0.0036	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P
PrimateAI	Benign	0.41	T
Vest4		0.10
MPC		0.63
ClinPred		0.018	T
GERP RS		2.7
gMVP		0.085

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: rs12688514; hg19: chrX-38144822; COSMIC: COSV58841320;