chrX-38323539-C-T

Position:

• chrX-38323539-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.29-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,202,845 control chromosomes in the GnomAD database, including 14,961 homozygotes. There are 59,659 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (2750 hom., 7210 hem., cov: 22)
  • Exomes 𝑓: 0.14 (12211 hom. 52449 hem.)
• Consequence: RPGR NM_001034853.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.50

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 (BayesDel_noAF=-0.86).
• BP6: Variant X-38323539-C-T is Benign according to our data. Variant chrX-38323539-C-T is described in ClinVar as [Benign]. Clinvar id is 92856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38323539-C-T is described in Lovd as [Benign]. Variant chrX-38323539-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.29-15G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.29-15G>A		splice_polypyrimidine_tract_variant, intron_variant			NM_001034853.2	ENSP00000495537	A2

Frequencies

GnomAD3 genomes AF: 0.218 AC: 24233 AN: 110988 Hom.: 2741 Cov.: 22 AF XY: 0.216 AC XY: 7178 AN XY: 33254

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.0751

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.218 AC: 39354 AN: 180770 Hom.: 4600 AF XY: 0.201 AC XY: 13240 AN XY: 65806

Gnomad AFR exome AF: 0.402

Gnomad AMR exome AF: 0.315

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.625

Gnomad SAS exome AF: 0.301

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.144 AC: 156798 AN: 1091805 Hom.: 12211 Cov.: 29 AF XY: 0.146 AC XY: 52449 AN XY: 359101

Gnomad4 AFR exome AF: 0.392

Gnomad4 AMR exome AF: 0.314

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.640

Gnomad4 SAS exome AF: 0.294

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.219 AC: 24275 AN: 111040 Hom.: 2750 Cov.: 22 AF XY: 0.216 AC XY: 7210 AN XY: 33316

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.619

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.105

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.194

Alfa AF: 0.143 Hom.: 3554

Bravo AF: 0.243

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 11, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.29-15G>A in intron 1 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 39.3% (1508/3833) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs6651585). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.11
DANN	Benign	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: rs6651585; hg19: chrX-38182792; COSMIC: COSV58840169; COSMIC: COSV58840169;