dbSNP rs147619484: RPGR:p.Glu741Asp (chrX-38286776-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001034853.2(RPGR):c.2223G>C(p.Glu741Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000095 in 1,052,754 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E741E) has been classified as Benign.

Frequency

Genomes: not found (cov: 16)

Exomes 𝑓: 9.5e-7 ( 0 hom. 1 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.27

Publications

4 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05919814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.2223G>C	p.Glu741Asp	missense_variant	Exon 15 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.2223G>C	p.Glu741Asp	missense_variant	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-379345C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.50e-7

AC:

AN:

1052754

Hom.:

Cov.:

AF XY:

0.00000291

AC XY:

AN XY:

343544

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24921

American (AMR)

AF:

0.00

AC:

AN:

27895

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18526

East Asian (EAS)

AF:

0.00

AC:

AN:

27200

South Asian (SAS)

AF:

0.00

AC:

AN:

49619

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3561

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819119

Other (OTH)

AF:

0.0000225

AC:

AN:

44365

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-1.1

CADD

Benign

2.0

(source)

DANN

Benign

0.43

FATHMM_MKL

Benign

0.045

LIST_S2

Benign

0.18

.;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.059

T;T

MetaSVM

Benign

-0.93

PhyloP100

-2.3

PrimateAI

Benign

0.20

PROVEAN

Benign

0.050

.;N

REVEL

Benign

0.016

Sift4G

Benign

0.33

.;T

Vest4

0.13

MutPred

0.30

Loss of helix (P = 0.4763);Loss of helix (P = 0.4763);

MVP

0.18

MPC

0.71

ClinPred

0.10

GERP RS

-2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.0053

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over