rs62640590

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.905G>C(p.Cys302Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,200,366 control chromosomes in the GnomAD database, including 2 homozygotes. There are 234 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C302R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., 110 hem., cov: 23)

Exomes 𝑓: 0.00044 ( 1 hom. 124 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.38

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 -16 ACMG points.

PM1

In a repeat RCC1 5 (size 51) in uniprot entity RPGR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001034853.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.024760395).

BP6

Variant X-38304664-C-G is Benign according to our data. Variant chrX-38304664-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 255837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38304664-C-G is described in Lovd as [Benign]. Variant chrX-38304664-C-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00334 (374/111891) while in subpopulation AFR AF= 0.0115 (354/30836). AF 95% confidence interval is 0.0105. There are 1 homozygotes in gnomad4. There are 110 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 110 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2 linkuse as main transcript	c.905G>C	p.Cys302Ser	missense_variant	8/15	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.905G>C	p.Cys302Ser	missense_variant	8/15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 linkuse as main transcript	c.172-361457C>G		intron_variant		5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

373

AN:

111837

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

110

AN XY:

34045

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000668

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:

0.0000751

Gnomad OTH

AF:

0.00603

GnomAD3 exomes

AF:

0.000989

AC:

180

AN:

181930

Hom.:

AF XY:

0.000734

AC XY:

AN XY:

66784

show subpopulations

Gnomad AFR exome

AF:

0.0117

Gnomad AMR exome

AF:

0.000658

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000741

Gnomad OTH exome

AF:

0.000892

GnomAD4 exome

AF:

0.000441

AC:

480

AN:

1088475

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

124

AN XY:

354841

show subpopulations

Gnomad4 AFR exome

AF:

0.0122

Gnomad4 AMR exome

AF:

0.000739

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000186

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000109

Gnomad4 OTH exome

AF:

0.000874

GnomAD4 genome

AF:

0.00334

AC:

374

AN:

111891

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

110

AN XY:

34109

show subpopulations

Gnomad4 AFR

AF:

0.0115

Gnomad4 AMR

AF:

0.000667

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000752

Gnomad4 OTH

AF:

0.00596

Alfa

AF:

0.000759

Hom.:

Bravo

AF:

0.00377

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00105

AC:

127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 13, 2022	Variant summary: RPGR c.905G>C (p.Cys302Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 181930 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote and 49 hemizygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RPGR causing X-linked Retinitis Pigmentosa (0.012 vs. 0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although c.905G>C has been reported in the literature in at least two individuals affected with Retinitis Pigmentosa (e.g. Wang_2014, Costa_2017), these reports do not provide unequivocal conclusions about association of the variant with X-linked Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2015	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 22, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

.;.;D;.;.;.;.;.;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

.;T;T;T;T;.;T;T;T

MetaRNN

Benign

0.025

T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.1

M;M;M;.;M;M;M;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.1

D;.;D;.;.;.;D;.;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;D;.;.;.;D;.;.

Polyphen

1.0

D;D;.;.;.;.;.;.;.

Vest4

0.88

MutPred

0.70

Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);.;Gain of disorder (P = 3e-04);

MVP

0.90

MPC

1.9

ClinPred

0.12

GERP RS

5.3

Varity_R

0.88

gMVP

0.98

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

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