rs606231180

Variant names:

• chrX-38285901-TCC-T
• rs606231180
• NM_001034853.2:c.3096_3097delGG

Your query was ambiguous. Multiple possible variants found:

• chrX-38285901-TCC-T
• chrX-38285901-TCC-TC
• chrX-38285901-TCC-TCCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001034853.2(RPGR):​c.3096_3097delGG​(p.Glu1033ArgfsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). The gene RPGR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: -0.117
• Publications: 3 publications found

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]

RPGR Gene-Disease associations (from GenCC):

• retinitis pigmentosa 3

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• RPGR-related retinopathy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• primary ciliary dyskinesia-retinitis pigmentosa syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• macular degeneration, X-linked atrophic

  Inheritance: XL Classification: LIMITED Submitted by: G2P

ENSG00000250349 (HGNC:):

ACMG classification

Specifications for RPGR are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 54 pathogenic variants in the truncated region.
• PP5: Variant X-38285901-TCC-T is Pathogenic according to our data. Variant chrX-38285901-TCC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 9910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034853.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	NM_001034853.2	MANE Select	c.3096_3097delGG	p.Glu1033ArgfsTer45	frameshift	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+1191_1905+1192delGG		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+1191_1902+1192delGG		intron	N/A	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.3096_3097delGG	p.Glu1033ArgfsTer45	frameshift	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-380216_172-380215delCC		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+1191_2520+1192delGG		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000279 AC: 3 AN: 1074426 Hom.: 0 AF XY: 0.00000289 AC XY: 1 AN XY: 346148

African (AFR) AF: 0.00 AC: 0 AN: 25823

American (AMR) AF: 0.00 AC: 0 AN: 32938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18982

East Asian (EAS) AF: 0.00 AC: 0 AN: 29314

South Asian (SAS) AF: 0.00 AC: 0 AN: 52616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4002

European-Non Finnish (NFE) AF: 0.00000362 AC: 3 AN: 829453

Other (OTH) AF: 0.00 AC: 0 AN: 45250

GnomAD4 genome Cov.: 17

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	X-linked cone-rod dystrophy 1 (3)
2	-	-	Retinitis pigmentosa 3 (2)
1	-	-	Cone dystrophy (1)
1	-	-	Cone dystrophy 1, X-linked (1)
1	-	-	Primary ciliary dyskinesia (1)
1	-	-	Retinal dystrophy (1)
1	-	-	RPGR-related disorder (1)
1	-	-	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.12
Mutation Taster		=10/190	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs606231180; hg19: chrX-38145154;