X-38318909-A-G

Variant names:

• chrX-38318909-A-G
• rs62638644
• NM_001034853.2:c.389T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001034853.2(RPGR):​c.389T>C​(p.Phe130Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.79

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891
• PP5: Variant X-38318909-A-G is Pathogenic according to our data. Variant chrX-38318909-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 813227.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chrX-38318909-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.389T>C	p.Phe130Ser	missense_variant	Exon 5 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.389T>C	p.Phe130Ser	missense_variant	Exon 5 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-347212A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Pathogenic:1

Jan 09, 2020

Molecular Genetics Laboratory, Institute for Ophthalmic Research

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Primary ciliary dyskinesia Uncertain:1

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 130 of the RPGR protein (p.Phe130Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 32531858). ClinVar contains an entry for this variant (Variation ID: 813227). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RPGR protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	.;.;T;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D;D;D;.;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	3.2	M;M;M;.;M;M;M;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.1	D;.;D;.;.;.;D;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.015	D;.;T;.;.;.;.;.;.
Sift4G	Uncertain	0.0040	D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;.;.;.;.;.;.;.
Vest4		0.87
MutPred		0.64		Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);Loss of stability (P = 0.0037);.;Loss of stability (P = 0.0037);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.99

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: rs62638644; hg19: chrX-38178162;