rs41305223

chrX-38301273-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034853.2(RPGR):c.1033A>G(p.Asn345Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,203,141 control chromosomes in the GnomAD database, including 51 homozygotes. There are 3,751 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. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0071 (2 hom., 204 hem., cov: 22)
  • Exomes 𝑓: 0.010 (49 hom. 3547 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.789

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0090559125).
• BP6: Variant X-38301273-T-C is Benign according to our data. Variant chrX-38301273-T-C is described in ClinVar as [Benign]. Clinvar id is 98725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38301273-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00709 (790/111478) while in subpopulation NFE AF= 0.0117 (622/53079). AF 95% confidence interval is 0.011. There are 2 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.1033A>G	p.Asn345Asp	missense_variant	9/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.1033A>G	p.Asn345Asp	missense_variant	9/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 791 AN: 111428 Hom.: 2 Cov.: 22 AF XY: 0.00609 AC XY: 205 AN XY: 33658

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00325

Gnomad ASJ AF: 0.00228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00667

GnomAD3 exomes AF: 0.00706 AC: 1268 AN: 179715 Hom.: 11 AF XY: 0.00660 AC XY: 426 AN XY: 64497

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00920

GnomAD4 exome AF: 0.0104 AC: 11320 AN: 1091663 Hom.: 49 Cov.: 27 AF XY: 0.00992 AC XY: 3547 AN XY: 357487

Gnomad4 AFR exome AF: 0.000875

Gnomad4 AMR exome AF: 0.00310

Gnomad4 ASJ exome AF: 0.00290

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.00742

Gnomad4 NFE exome AF: 0.0124

Gnomad4 OTH exome AF: 0.00822

GnomAD4 genome AF: 0.00709 AC: 790 AN: 111478 Hom.: 2 Cov.: 22 AF XY: 0.00605 AC XY: 204 AN XY: 33718

Gnomad4 AFR AF: 0.00225

Gnomad4 AMR AF: 0.00325

Gnomad4 ASJ AF: 0.00228

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00151

Gnomad4 FIN AF: 0.00754

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.00658

Alfa AF: 0.0104 Hom.: 483

Bravo AF: 0.00635

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0145 AC: 42

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.0109 AC: 73

ExAC AF: 0.00760 AC: 922

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2018	This variant is associated with the following publications: (PMID: 10937588, 11857109) -
not provided, no classification provided	literature only	Retina International	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	4.7
Dann	Benign	0.89
FATHMM_MKL	Benign	0.51	D
MetaRNN	Benign	0.0091	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L;L;L;.;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N;.;N;.;.;.;N;.
REVEL	Benign	0.24
Sift	Benign	0.34	T;.;T;.;.;.;.;.
Sift4G	Benign	0.40	T;.;T;.;.;.;T;.
Polyphen		0.020	B;B;.;.;.;.;.;.
Vest4		0.12
MVP		0.64
MPC		1.1
ClinPred		0.013	T
GERP RS		-3.1
Varity_R		0.25
gMVP		0.76

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: rs41305223; hg19: chrX-38160526; COSMIC: COSV58834282; COSMIC: COSV58834282;