rs1060501180

Positions:

• chrX-38318846-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001034853.2(RPGR):​c.452C>T​(p.Thr151Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,866 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.452C>T	p.Thr151Ile	missense_variant	5/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.452C>T	p.Thr151Ile	missense_variant	5/15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-347275G>A		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097866 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2016

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RPGR-related disease. This sequence change replaces threonine with isoleucine at codon 151 of the RPGR protein (p.Thr151Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;.;D;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.5	L;L;L;.;L;L;L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.8	D;.;D;.;.;.;D;.;.
REVEL	Uncertain	0.59
Sift	Benign	0.12	T;.;T;.;.;.;.;.;.
Sift4G	Uncertain	0.0080	D;.;D;.;.;.;D;.;.
Polyphen		0.57	P;P;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.64		Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);Loss of disorder (P = 0.0325);.;Loss of disorder (P = 0.0325);
MVP		0.88
MPC		1.3
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.76
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1060501180; hg19: chrX-38178099;