chrX-38275092-T-C

Position:

• chrX-38275092-T-C

Variant summary

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

The NM_000328.3(RPGR):​c.2146A>G​(p.Lys716Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,205,545 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 76 hem.)
• Consequence: RPGR NM_000328.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.24

Genes affected

ENSG00000250349 (HGNC:):

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=0.010278642).
• BP6: Variant X-38275092-T-C is Benign according to our data. Variant chrX-38275092-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 414010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_000328.3	c.2146A>G	p.Lys716Glu	missense_variant	17/19		NP_000319.1
RPGR	NM_001367245.1	c.2143A>G	p.Lys715Glu	missense_variant	17/19		NP_001354174.1
RPGR	NM_001367246.1	c.1960A>G	p.Lys654Glu	missense_variant	16/18		NP_001354175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1	c.172-391029T>C		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0000536 AC: 6 AN: 111846 Hom.: 0 Cov.: 23 AF XY: 0.0000588 AC XY: 2 AN XY: 34008

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000224 AC: 41 AN: 183001 Hom.: 0 AF XY: 0.000355 AC XY: 24 AN XY: 67525

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00215

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 130 AN: 1093646 Hom.: 0 Cov.: 28 AF XY: 0.000212 AC XY: 76 AN XY: 359310

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: 0.00235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000536 AC: 6 AN: 111899 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34071

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00226

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000197 Hom.: 2

Bravo AF: 0.0000113

ExAC AF: 0.000362 AC: 44

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 01, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	.;.;T;.;.
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	.;T;T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	.;.;L;.;.
PROVEAN	Benign	-0.65	N;.;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.39	T;.;T;.;.
Sift4G	Benign	0.43	T;.;T;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.38
MutPred		0.20		Loss of ubiquitination at K716 (P = 9e-04);Loss of ubiquitination at K716 (P = 9e-04);.;.;.;
MVP		0.44
ClinPred		0.10	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs771791722; hg19: chrX-38134345;