rs147388235

chrX-38286588-C-T

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.2411G>A(p.Arg804Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,041,819 control chromosomes in the GnomAD database, including 26 homozygotes. There are 334 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (9 hom., 37 hem., cov: 8)
  • Exomes 𝑓: 0.0012 (17 hom. 297 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.17

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=0.0029108226).
• BP6: Variant X-38286588-C-T is Benign according to our data. Variant chrX-38286588-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00789 (376/47676) while in subpopulation AFR AF= 0.0305 (353/11571). AF 95% confidence interval is 0.0279. There are 9 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.2411G>A	p.Arg804Lys	missense_variant	15/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.2411G>A	p.Arg804Lys	missense_variant	15/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 376 AN: 47655 Hom.: 9 Cov.: 8 AF XY: 0.00825 AC XY: 37 AN XY: 4485

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00384

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000160

Gnomad OTH AF: 0.00467

GnomAD3 exomes AF: 0.00349 AC: 352 AN: 100892 Hom.: 8 AF XY: 0.00219 AC XY: 67 AN XY: 30656

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000535

Gnomad OTH exome AF: 0.00241

GnomAD4 exome AF: 0.00122 AC: 1212 AN: 994143 Hom.: 17 Cov.: 33 AF XY: 0.000965 AC XY: 297 AN XY: 307641

Gnomad4 AFR exome AF: 0.0412

Gnomad4 AMR exome AF: 0.00345

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000152

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000398

Gnomad4 OTH exome AF: 0.00325

GnomAD4 genome AF: 0.00789 AC: 376 AN: 47676 Hom.: 9 Cov.: 8 AF XY: 0.00821 AC XY: 37 AN XY: 4506

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00383

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000160

Gnomad4 OTH AF: 0.00458

Alfa AF: 0.00188 Hom.: 32

ESP6500AA AF: 0.0351 AC: 114

ESP6500EA AF: 0.000539 AC: 3

ExAC AF: 0.00407 AC: 136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 24, 2019	- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.2
Cadd	Benign	0.0030
Dann	Benign	0.44
FATHMM_MKL	Benign	0.0010	N
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.20	T
Vest4		0.031
MVP		0.10
MPC		0.79
ClinPred		0.0015	T
GERP RS		-0.92
gMVP		0.0024

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: rs147388235; hg19: chrX-38145841;