rs45486397

Positions:

• chrX-38310814-A-G

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.620-41T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,174,410 control chromosomes in the GnomAD database, including 239 homozygotes. There are 5,265 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (95 hom., 1004 hem., cov: 23)
  • Exomes 𝑓: 0.012 (144 hom. 4261 hem.)
• Consequence: RPGR NM_001034853.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.302

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant X-38310814-A-G is Benign according to our data. Variant chrX-38310814-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 98793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38310814-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.620-41T>C		intron_variant		ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.620-41T>C		intron_variant			NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-355307A>G		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 3614 AN: 112095 Hom.: 95 Cov.: 23 AF XY: 0.0293 AC XY: 1004 AN XY: 34271

Gnomad AFR AF: 0.0911

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0195

Gnomad ASJ AF: 0.0140

Gnomad EAS AF: 0.000278

Gnomad SAS AF: 0.0156

Gnomad FIN AF: 0.00504

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.00838

Gnomad OTH AF: 0.0305

GnomAD3 exomes AF: 0.0163 AC: 2838 AN: 174074 Hom.: 54 AF XY: 0.0148 AC XY: 881 AN XY: 59586

Gnomad AFR exome AF: 0.0954

Gnomad AMR exome AF: 0.00886

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.00104

Gnomad SAS exome AF: 0.0233

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.00910

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0123 AC: 13071 AN: 1062259 Hom.: 144 Cov.: 25 AF XY: 0.0129 AC XY: 4261 AN XY: 331343

Gnomad4 AFR exome AF: 0.104

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0178

Gnomad4 EAS exome AF: 0.000634

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.00587

Gnomad4 NFE exome AF: 0.00917

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0322 AC: 3612 AN: 112151 Hom.: 95 Cov.: 23 AF XY: 0.0292 AC XY: 1004 AN XY: 34337

Gnomad4 AFR AF: 0.0910

Gnomad4 AMR AF: 0.0194

Gnomad4 ASJ AF: 0.0140

Gnomad4 EAS AF: 0.000279

Gnomad4 SAS AF: 0.0156

Gnomad4 FIN AF: 0.00504

Gnomad4 NFE AF: 0.00836

Gnomad4 OTH AF: 0.0295

Alfa AF: 0.0208 Hom.: 150

Bravo AF: 0.0381

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.67

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: rs45486397; hg19: chrX-38170067;