rs200824587

Positions:

• chrX-38286378-CCTTCCTCCCCTTCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM4 BP6

The NM_001034853.2(RPGR):​c.2606_2620delAAGAAGGGGAGGAAG​(p.Glu869_Glu873del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., 1 hem., cov: 5)
  • Exomes 𝑓: 0.0064 (53 hom. 1399 hem.)
  • Failed GnomAD Quality Control
• Consequence: RPGR NM_001034853.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.04

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 1 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001034853.2.
• BP6: Variant X-38286378-CCTTCCTCCCCTTCTT-C is Benign according to our data. Variant chrX-38286378-CCTTCCTCCCCTTCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237686.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=3}. Variant chrX-38286378-CCTTCCTCCCCTTCTT-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.2606_2620delAAGAAGGGGAGGAAG	p.Glu869_Glu873del	disruptive_inframe_deletion	15/15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.2606_2620delAAGAAGGGGAGGAAG	p.Glu869_Glu873del	disruptive_inframe_deletion	15/15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-379741_172-379727delTTCCTCCCCTTCTTC		intron_variant		5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 78 AN: 22175 Hom.: 0 Cov.: 5 AF XY: 0.000934 AC XY: 1 AN XY: 1071

Gnomad AFR AF: 0.000549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00276

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000575 AC: 24 AN: 41741 Hom.: 0 AF XY: 0.000164 AC XY: 1 AN XY: 6103

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.000687

Gnomad ASJ exome AF: 0.000547

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000717

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00644 AC: 4453 AN: 690972 Hom.: 53 AF XY: 0.00743 AC XY: 1399 AN XY: 188180

Gnomad4 AFR exome AF: 0.000945

Gnomad4 AMR exome AF: 0.00508

Gnomad4 ASJ exome AF: 0.0274

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.0242

Gnomad4 NFE exome AF: 0.00611

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00352 AC: 78 AN: 22180 Hom.: 0 Cov.: 5 AF XY: 0.000929 AC XY: 1 AN XY: 1076

Gnomad4 AFR AF: 0.000549

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00376

Gnomad4 NFE AF: 0.00515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00836 Hom.: 64

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	RPGR: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 07, 2016	- -

X-linked cone-rod dystrophy 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

DBGen Ocular Genomics

Jan 01, 2021

Class 3 ACMG Guidelines, 2015 -

Primary ciliary dyskinesia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 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: rs200824587; hg19: chrX-38145631;