rs62640590

chrX-38304664-C-GchrX-38304664-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• PM1: In a repeat RCC1 5 (size 51) in uniprot entity RPGR_HUMAN there are 22 pathogenic changes around while only 4 benign (85%) in NM_001034853.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38304665-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 98809.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 110 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.905G>C	p.Cys302Ser	missense_variant	8/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.905G>C	p.Cys302Ser	missense_variant	8/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 373 AN: 111837 Hom.: 1 Cov.: 23 AF XY: 0.00323 AC XY: 110 AN XY: 34045

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.: 1 AF XY: 0.000734 AC XY: 49 AN XY: 66784

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.: 1 Cov.: 27 AF XY: 0.000349 AC XY: 124 AN XY: 354841

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.: 1 Cov.: 23 AF XY: 0.00322 AC XY: 110 AN XY: 34109

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.: 13

Bravo AF: 0.00377

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.0120 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00105 AC: 127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jul 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Uncertain	23
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.025	T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.1	M;M;M;.;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
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	T
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

Other links and lift over

dbSNP: rs62640590; hg19: chrX-38163917;