chrX-38323412-A-C

Position:

• chrX-38323412-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001034853.2(RPGR):​c.141T>G​(p.Ser47Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000425 in 1,204,786 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 162 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., 15 hem., cov: 23)
  • Exomes 𝑓: 0.00043 (0 hom. 147 hem.)
• Consequence: RPGR NM_001034853.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.471

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-38323412-A-C is Benign according to our data. Variant chrX-38323412-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 98741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-38323412-A-C is described in Lovd as [Likely_benign]. Variant chrX-38323412-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.471 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00043 (470/1092373) while in subpopulation MID AF= 0.00927 (38/4099). AF 95% confidence interval is 0.00694. There are 0 homozygotes in gnomad4_exome. There are 147 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.141T>G	p.Ser47Ser	synonymous_variant	2/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.141T>G	p.Ser47Ser	synonymous_variant	2/15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-342709A>C		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 42 AN: 112359 Hom.: 0 Cov.: 23 AF XY: 0.000435 AC XY: 15 AN XY: 34495

Gnomad AFR AF: 0.0000971

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00123

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000365

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000300

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000514 AC: 92 AN: 178920 Hom.: 0 AF XY: 0.000487 AC XY: 31 AN XY: 63654

Gnomad AFR exome AF: 0.0000773

Gnomad AMR exome AF: 0.000478

Gnomad ASJ exome AF: 0.00352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000632

Gnomad NFE exome AF: 0.000594

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000430 AC: 470 AN: 1092373 Hom.: 0 Cov.: 28 AF XY: 0.000411 AC XY: 147 AN XY: 358095

Gnomad4 AFR exome AF: 0.000570

Gnomad4 AMR exome AF: 0.000569

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.000112

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000374 AC: 42 AN: 112413 Hom.: 0 Cov.: 23 AF XY: 0.000434 AC XY: 15 AN XY: 34559

Gnomad4 AFR AF: 0.0000969

Gnomad4 AMR AF: 0.00122

Gnomad4 ASJ AF: 0.00264

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000366

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.000300

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000781 Hom.: 3

Bravo AF: 0.000359

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 07, 2016	p.Ser47Ser in exon 2 of RPGR: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.1% (47/34663) of E uropean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs62638631). -

not provided Benign:3 Other:1

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	Retina International	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	RPGR: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 25, 2015	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 26, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	2.8
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs62638631; hg19: chrX-38182665;