dbSNP rs147388235: RPGR:p.Arg804Lys (chrX-38286588-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.2411G>A(p.Arg804Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,041,819 control chromosomes in the GnomAD database, including 26 homozygotes. There are 334 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene RPGR is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0079 ( 9 hom., 37 hem., cov: 8)

Exomes 𝑓: 0.0012 ( 17 hom. 297 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:5

Conservation

PhyloP100: -1.17

Publications

0 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), PanelApp Australia
RPGR-related retinopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
primary ciliary dyskinesia-retinitis pigmentosa syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
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

Specifications for RPGR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029108226).

BP6

Variant X-38286588-C-T is Benign according to our data. Variant chrX-38286588-C-T is described in ClinVar as Benign. ClinVar VariationId is 446001.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00789 (376/47676) while in subpopulation AFR AF = 0.0305 (353/11571). AF 95% confidence interval is 0.0279. There are 9 homozygotes in GnomAd4. There are 37 alleles in the male GnomAd4 subpopulation. Median coverage is 8. This position passed quality control check.

BS2

High AC in GnomAd4 at 376 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	NM_001034853.2	MANE Select	c.2411G>A	p.Arg804Lys	missense	Exon 15 of 15	NP_001030025.1	Q92834-6
RPGR	NM_000328.3		c.1905+506G>A		intron	N/A	NP_000319.1	Q92834-2
RPGR	NM_001367245.1		c.1902+506G>A		intron	N/A	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	ENST00000645032.1	MANE Select	c.2411G>A	p.Arg804Lys	missense	Exon 15 of 15	ENSP00000495537.1	Q92834-6
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-379533C>T		intron	N/A	ENSP00000417050.1	B4E171
RPGR	ENST00000339363.7	TSL:5	c.2520+506G>A		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes

AF:

0.00789

AC:

376

AN:

47655

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0305

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00384

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000160

Gnomad OTH

AF:

0.00467

GnomAD2 exomes

AF:

0.00349

AC:

352

AN:

100892

AF XY:

0.00219

show subpopulations

Gnomad AFR exome

AF:

0.0424

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000535

Gnomad OTH exome

AF:

0.00241

GnomAD4 exome

AF:

0.00122

AC:

1212

AN:

994143

Hom.:

Cov.:

AF XY:

0.000965

AC XY:

297

AN XY:

307641

show subpopulations

African (AFR)

AF:

0.0412

AC:

953

AN:

23111

American (AMR)

AF:

0.00345

AC:

AN:

24900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16677

East Asian (EAS)

AF:

0.00

AC:

AN:

24845

South Asian (SAS)

AF:

0.000152

AC:

AN:

46151

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35015

Middle Eastern (MID)

AF:

0.000381

AC:

AN:

2622

European-Non Finnish (NFE)

AF:

0.0000398

AC:

AN:

779609

Other (OTH)

AF:

0.00325

AC:

134

AN:

41213

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

148

197

246

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00789

AC:

376

AN:

47676

Hom.:

Cov.:

AF XY:

0.00821

AC XY:

AN XY:

4506

show subpopulations

African (AFR)

AF:

0.0305

AC:

353

AN:

11571

American (AMR)

AF:

0.00383

AC:

AN:

4178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1272

East Asian (EAS)

AF:

0.00

AC:

AN:

1531

South Asian (SAS)

AF:

0.00

AC:

AN:

670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000160

AC:

AN:

25024

Other (OTH)

AF:

0.00458

AC:

AN:

655

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.557

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00188

Hom.:

ESP6500AA

AF:

0.0351

AC:

114

ESP6500EA

AF:

0.000539

AC:

ExAC

AF:

0.00407

AC:

136

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Primary ciliary dyskinesia (1)

RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-1.0

BayesDel_noAF

Benign

-1.2

CADD

Benign

0.0030

(source)

DANN

Benign

0.44

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.92

PhyloP100

-1.2

PrimateAI

Benign

0.20

PROVEAN

Benign

0.23

REVEL

Benign

0.011

Sift4G

Benign

1.0

Vest4

0.031

MVP

0.10

MPC

0.79

ClinPred

0.0015

GERP RS

-0.92

gMVP

0.0024

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over