chrX-38285905-CCT-C

Variant names:

• chrX-38285905-CCT-C
• rs606231181
• NM_001034853.2:c.3092_3093delAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001034853.2(RPGR):​c.3092_3093delAG​(p.Glu1031GlyfsTer47) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000931 in 1,074,310 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: RPGR NM_001034853.2 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: -0.177
• Publications: 7 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

Our verdict: Pathogenic. The variant received 18 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 56 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38285905-CCT-C is Pathogenic according to our data. Variant chrX-38285905-CCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9911.Status of the report is reviewed_by_expert_panel, 3 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.3092_3093delAG	p.Glu1031GlyfsTer47	frameshift	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+1187_1905+1188delAG		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+1187_1902+1188delAG		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.3092_3093delAG	p.Glu1031GlyfsTer47	frameshift	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-380212_172-380211delTC		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+1187_2520+1188delAG		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 9.31e-7 AC: 1 AN: 1074310 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 347360

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25861

American (AMR) AF: 0.0000309 AC: 1 AN: 32401

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19021

East Asian (EAS) AF: 0.00 AC: 0 AN: 29162

South Asian (SAS) AF: 0.00 AC: 0 AN: 52344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35411

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3988

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 830816

Other (OTH) AF: 0.00 AC: 0 AN: 45306

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 16

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=6/194	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: rs606231181; hg19: chrX-38145158;