rs147649203

chrX-38269751-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000339363.7(RPGR):c.2938A>G(p.Ile980Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,207,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict 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. I980T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00020 (0 hom. 57 hem.)
• Consequence: RPGR ENST00000339363.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.671

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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017639518).
• BP6: Variant X-38269751-T-C is Benign according to our data. Variant chrX-38269751-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 237687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38269751-T-C is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_000328.3	c.2323A>G	p.Ile775Val	missense_variant	19/19
RPGR	NM_001367245.1	c.2320A>G	p.Ile774Val	missense_variant	19/19
RPGR	NM_001367246.1	c.2137A>G	p.Ile713Val	missense_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000339363.7	c.2938A>G	p.Ile980Val	missense_variant	18/18	5		P4
RPGR	ENST00000642395.2	c.2323A>G	p.Ile775Val	missense_variant	19/19			A2
RPGR	ENST00000644337.1	c.2137A>G	p.Ile713Val	missense_variant	18/18

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 32 AN: 111944 Hom.: 0 Cov.: 23 AF XY: 0.000235 AC XY: 8 AN XY: 34084

Gnomad AFR AF: 0.000780

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000113

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000191 AC: 35 AN: 183156 Hom.: 0 AF XY: 0.000177 AC XY: 12 AN XY: 67686

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 216 AN: 1095805 Hom.: 0 Cov.: 29 AF XY: 0.000158 AC XY: 57 AN XY: 361287

Gnomad4 AFR exome AF: 0.000949

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000370

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.000456

GnomAD4 genome AF: 0.000286 AC: 32 AN: 111998 Hom.: 0 Cov.: 23 AF XY: 0.000234 AC XY: 8 AN XY: 34148

Gnomad4 AFR AF: 0.000779

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000208 Hom.: 12

Bravo AF: 0.000419

ESP6500AA AF: 0.000783 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 06, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 01, 2022	This alteration is classified as likely 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

PreventionGenetics, part of Exact Sciences

Dec 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.93
Dann	Benign	0.46
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-0.060	N;.;N;.;.
REVEL	Benign	0.039
Sift	Benign	0.46	T;.;D;.;.
Sift4G	Benign	0.42	T;.;T;.;.
Polyphen		0.0070	B;B;.;.;.
Vest4		0.068
MVP		0.11
ClinPred		0.0039	T
GERP RS		-2.2
Varity_R		0.061

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: rs147649203; hg19: chrX-38129004;