rs398123335

Positions:

chrX-38288032-TTTG-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.1579_1581delCAA(p.Gln527del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0228 in 1,206,736 control chromosomes in the GnomAD database, including 280 homozygotes. There are 8,407 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 38 hom., 594 hem., cov: 21)

Exomes 𝑓: 0.023 ( 242 hom. 7813 hem. )

Consequence

RPGR
NM_001034853.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 5.33

Variant links:

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]

RPGR links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001034853.2. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant X-38288032-TTTG-T is Benign according to our data. Variant chrX-38288032-TTTG-T is described in ClinVar as [Likely_benign]. Clinvar id is 92853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38288032-TTTG-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0196 (2195/112164) while in subpopulation NFE AF= 0.0288 (1531/53245). AF 95% confidence interval is 0.0276. There are 38 homozygotes in gnomad4. There are 594 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 38 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2 linkuse as main transcript	c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	14/15	ENST00000645032.1	NP_001030025.1	Q92834-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 linkuse as main transcript	c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	14/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-378083_172-378081delGTT		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2195

AN:

112113

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

593

AN XY:

34267

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.0427

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000738

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0417

Gnomad NFE

AF:

0.0287

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0183

AC:

3341

AN:

182433

Hom.:

AF XY:

0.0169

AC XY:

1133

AN XY:

67179

show subpopulations

Gnomad AFR exome

AF:

0.00396

Gnomad AMR exome

AF:

0.0125

Gnomad ASJ exome

AF:

0.0439

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.00315

Gnomad FIN exome

AF:

0.0183

Gnomad NFE exome

AF:

0.0263

Gnomad OTH exome

AF:

0.0287

GnomAD4 exome

AF:

0.0232

AC:

25343

AN:

1094572

Hom.:

242

AF XY:

0.0216

AC XY:

7813

AN XY:

361364

show subpopulations

Gnomad4 AFR exome

AF:

0.00379

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.0407

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00338

Gnomad4 FIN exome

AF:

0.0210

Gnomad4 NFE exome

AF:

0.0260

Gnomad4 OTH exome

AF:

0.0224

GnomAD4 genome

AF:

0.0196

AC:

2195

AN:

112164

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

594

AN XY:

34328

show subpopulations

Gnomad4 AFR

AF:

0.00346

Gnomad4 AMR

AF:

0.0157

Gnomad4 ASJ

AF:

0.0427

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000740

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.0288

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0280

Hom.:

226

Bravo

AF:

0.0190

Asia WGS

AF:

0.00438

AC:

AN:

2522

EpiCase

AF:

0.0281

EpiControl

AF:

0.0276

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 03, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 29, 2016	p.Gln527del in exon 14 of RPGR: This variant is not expected to have clinical si gnificance because it has been identified in 2.8% (1333/46868) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs398123335). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2024	Variant summary: RPGR c.1579_1581delCAA (p.Gln527del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.018 in 182433 control chromosomes, predominantly at a frequency of 0.026 within the Non-Finnish European subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGR causing Retinitis Pigmentosa, X-Linked phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1579_1581delCAA has been reported in the literature studying genetic susceptibility of Pulmonary Nontuberculous Mycobacterial Infectioin, without further information for analysis (Szymanski_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa, X-Linked. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26038974). ClinVar contains an entry for this variant (Variation ID: 92853. Benign/Likely Benign). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 18, 2019	This variant is associated with the following publications: (PMID: 26038974) -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over