rs28718831

Positions:

• chrX-38297402-T-A

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.1296A>T​(p.Glu432Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,206,029 control chromosomes in the GnomAD database, including 13 homozygotes. There are 385 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (5 hom., 186 hem., cov: 21)
  • Exomes 𝑓: 0.00072 (8 hom. 199 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.15

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=0.002887547).
• BP6: Variant X-38297402-T-A is Benign according to our data. Variant chrX-38297402-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 255832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00661 (727/110013) while in subpopulation AFR AF= 0.0232 (701/30225). AF 95% confidence interval is 0.0218. There are 5 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.1296A>T	p.Glu432Asp	missense_variant	11/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.1296A>T	p.Glu432Asp	missense_variant	11/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 725 AN: 109961 Hom.: 5 Cov.: 21 AF XY: 0.00574 AC XY: 185 AN XY: 32217

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

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: 0.00272

GnomAD3 exomes AF: 0.00195 AC: 357 AN: 183212 Hom.: 4 AF XY: 0.00105 AC XY: 71 AN XY: 67708

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.000948

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000525

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000724 AC: 793 AN: 1096016 Hom.: 8 Cov.: 29 AF XY: 0.000551 AC XY: 199 AN XY: 361442

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00105

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.00198

GnomAD4 genome AF: 0.00661 AC: 727 AN: 110013 Hom.: 5 Cov.: 21 AF XY: 0.00576 AC XY: 186 AN XY: 32279

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00216

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: 0.00269

Alfa AF: 0.00111 Hom.: 22

Bravo AF: 0.00771

ESP6500AA AF: 0.0284 AC: 109

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00217 AC: 263

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 05, 2015	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. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

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	0.15
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.97
FATHMM_MKL	Benign	0.085	N
MetaRNN	Benign	0.0029	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L;.;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;.;N;.;.;.;N
REVEL	Benign	0.0090
Sift	Benign	0.11	T;.;T;.;.;.;.
Sift4G	Benign	0.56	T;.;T;.;.;.;T
Polyphen		0.024	B;B;.;.;.;.;.
Vest4		0.12
MutPred		0.14		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.10
MPC		0.044
ClinPred		0.0018	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.17

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: rs28718831; hg19: chrX-38156655;