rs398123335

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

retinitis pigmentosa 3
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
RPGR-related retinopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
primary ciliary dyskinesia-retinitis pigmentosa syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
macular degeneration, X-linked atrophic
Inheritance: XL Classification: LIMITED Submitted by: G2P

RPGR links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High AC in GnomAd4 at 2195 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	Exon 14 of 15	ENST00000645032.1	NP_001030025.1	Q92834-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 link	c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	Exon 14 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-378083_172-378081delGTT		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2195

AN:

112113

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0183

AC:

3341

AN:

182433

AF XY:

0.0169

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00379

AC:

100

AN:

26364

American (AMR)

AF:

0.0131

AC:

461

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.0407

AC:

788

AN:

19342

East Asian (EAS)

AF:

0.00

AC:

AN:

30192

South Asian (SAS)

AF:

0.00338

AC:

183

AN:

54091

European-Finnish (FIN)

AF:

0.0210

AC:

846

AN:

40372

Middle Eastern (MID)

AF:

0.0389

AC:

160

AN:

4109

European-Non Finnish (NFE)

AF:

0.0260

AC:

21777

AN:

838924

Other (OTH)

AF:

0.0224

AC:

1028

AN:

45994

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.389

Heterozygous variant carriers

773

1545

2318

3090

3863

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0196

AC:

2195

AN:

112164

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

594

AN XY:

34328

show subpopulations

African (AFR)

AF:

0.00346

AC:

107

AN:

30946

American (AMR)

AF:

0.0157

AC:

166

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.0427

AC:

113

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.000740

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.0186

AC:

113

AN:

6059

Middle Eastern (MID)

AF:

0.0411

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0288

AC:

1531

AN:

53245

Other (OTH)

AF:

0.0151

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

165

248

330

413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jan 13, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

not provided

Benign:2Other:1

Retina International

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 18, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26038974) -

Primary ciliary dyskinesia

Benign:2

Dec 26, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.3

Mutation Taster

=82/18

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over