rs777850798

Positions:

• chrX-38286537-TCCTCTACTTCCCCTC-T
• chrX-38286537-TCCTCTACTTCCCCTC-TCCTCTACTTCCCCTCCCTCTACTTCCCCTC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BS1 BS2

The NM_001034853.2(RPGR):​c.2447_2461del​(p.Gly816_Glu820del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 896,827 control chromosomes in the GnomAD database, including 7 homozygotes. There are 907 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., 0 hem., cov: 4)
  • Exomes 𝑓: 0.0035 (7 hom. 907 hem.)
• Consequence: RPGR NM_001034853.2 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: 1.59

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 Likely_benign. Variant got -6 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001034853.2.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00354 (3064/864447) while in subpopulation NFE AF= 0.0041 (2835/691275). AF 95% confidence interval is 0.00397. There are 7 homozygotes in gnomad4_exome. There are 907 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPGR	NM_001034853.2	c.2447_2461del	p.Gly816_Glu820del	inframe_deletion	15/15	ENST00000645032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPGR	ENST00000645032.1	c.2447_2461del	p.Gly816_Glu820del	inframe_deletion	15/15		NM_001034853.2	A2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 58 AN: 32387 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 1997

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00266

GnomAD3 exomes AF: 0.00114 AC: 105 AN: 91821 Hom.: 0 AF XY: 0.000651 AC XY: 16 AN XY: 24565

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.000271

Gnomad SAS exome AF: 0.000497

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00240

Gnomad OTH exome AF: 0.000749

GnomAD4 exome AF: 0.00354 AC: 3064 AN: 864447 Hom.: 7 AF XY: 0.00347 AC XY: 907 AN XY: 261387

Gnomad4 AFR exome AF: 0.00202

Gnomad4 AMR exome AF: 0.000920

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00108

Gnomad4 SAS exome AF: 0.000787

Gnomad4 FIN exome AF: 0.000448

Gnomad4 NFE exome AF: 0.00410

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00179 AC: 58 AN: 32380 Hom.: 0 Cov.: 4 AF XY: 0.00 AC XY: 0 AN XY: 2000

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00341

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00260

Alfa AF: 0.00115 Hom.: 8

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	RPGR: BS2 -

X-linked cone-rod dystrophy 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2002

- -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs777850798; hg19: chrX-38145790;