rs112368541

Positions:

• chrX-38269840-A-G

Variant summary

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

The NM_000328.3(RPGR):​c.2242-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,122,026 control chromosomes in the GnomAD database, including 24 homozygotes. There are 584 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., 298 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (12 hom. 286 hem.)
• Consequence: RPGR NM_000328.3 splice_region, intron
• Scores: Splicing: ADA: 0.0008426
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.87

Genes affected

ENSG00000250349 (HGNC:):

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=-0.84).
• BP6: Variant X-38269840-A-G is Benign according to our data. Variant chrX-38269840-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 227049.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 = 0.0101 (1131/112217) while in subpopulation AFR AF= 0.0353 (1090/30841). AF 95% confidence interval is 0.0336. There are 12 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_000328.3	c.2242-8T>C		splice_region_variant, intron_variant			NP_000319.1
RPGR	NM_001367245.1	c.2239-8T>C		splice_region_variant, intron_variant			NP_001354174.1
RPGR	NM_001367246.1	c.2056-8T>C		splice_region_variant, intron_variant			NP_001354175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-396281A>G		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1127 AN: 112164 Hom.: 11 Cov.: 23 AF XY: 0.00863 AC XY: 296 AN XY: 34310

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00226

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00596

GnomAD3 exomes AF: 0.00302 AC: 506 AN: 167626 Hom.: 6 AF XY: 0.00217 AC XY: 122 AN XY: 56104

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00113 AC: 1146 AN: 1009809 Hom.: 12 Cov.: 24 AF XY: 0.000975 AC XY: 286 AN XY: 293433

Gnomad4 AFR exome AF: 0.0369

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.0000530

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000966

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000850

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.0101 AC: 1131 AN: 112217 Hom.: 12 Cov.: 23 AF XY: 0.00867 AC XY: 298 AN XY: 34373

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.00226

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00589

Alfa AF: 0.00600 Hom.: 29

Bravo AF: 0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	2242-8T>C in intron 18A of RPGR: This variant is not expected to have clinical s ignificance because it has been identified in 3.3% (125/3788) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs112368541). -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.4
DANN	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00084
dbscSNV1_RF	Benign	0.026
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: rs112368541; hg19: chrX-38129093;