X-38304704-T-G

Position:

• chrX-38304704-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_001034853.2(RPGR):​c.865A>C​(p.Ile289Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000894 in 111,869 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I289V) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550

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 4 ACMG points.

• PM1: In a repeat RCC1 5 (size 51) in uniprot entity RPGR_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001034853.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.11411759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.865A>C	p.Ile289Leu	missense_variant	8/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.865A>C	p.Ile289Leu	missense_variant	8/15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-361417T>G		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.00000894 AC: 1 AN: 111869 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34013

Gnomad AFR AF: 0.0000325

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.00000894 AC: 1 AN: 111869 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34013

Gnomad4 AFR AF: 0.0000325

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.060
DANN	Benign	0.80
DEOGEN2	Benign	0.23	.;.;T;.;.;.;.;.;.
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.62	.;T;T;T;T;.;T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.15	N;N;N;.;N;N;N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N;.;N;.;.;.;N;.;.
REVEL	Benign	0.19
Sift	Benign	0.16	T;.;T;.;.;.;.;.;.
Sift4G	Uncertain	0.017	D;.;D;.;.;.;D;.;.
Polyphen		0.077	B;B;.;.;.;.;.;.;.
Vest4		0.27
MutPred		0.48		Gain of ubiquitination at K287 (P = 0.0661);Gain of ubiquitination at K287 (P = 0.0661);Gain of ubiquitination at K287 (P = 0.0661);Gain of ubiquitination at K287 (P = 0.0661);Gain of ubiquitination at K287 (P = 0.0661);Gain of ubiquitination at K287 (P = 0.0661);Gain of ubiquitination at K287 (P = 0.0661);.;Gain of ubiquitination at K287 (P = 0.0661);
MVP		0.33
MPC		0.86
ClinPred		0.22	T
GERP RS		-2.8
Varity_R		0.28
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs62640587; hg19: chrX-38163957;