rs62653033

Variant names:

• chrX-38288032-TTTG-T
• rs62653033
• NM_001034853.2:c.1579_1581delCAA

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BS1 BS2

The NM_001034853.2(RPGR):​c.1579_1581delCAA​(p.Gln527del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0228 in 1,206,736 control chromosomes in the GnomAD database, including 280 homozygotes. There are 8,407 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (38 hom., 594 hem., cov: 21)
  • Exomes 𝑓: 0.023 (242 hom. 7813 hem.)
• Consequence: RPGR NM_001034853.2 conservative_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 5.33
• Publications: 1 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: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001034853.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-38288032-TTTG-T is Benign according to our data. Variant chrX-38288032-TTTG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92853.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0196 (2195/112164) while in subpopulation NFE AF = 0.0288 (1531/53245). AF 95% confidence interval is 0.0276. There are 38 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2195 XL,AD gene.

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.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	Exon 14 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	Exon 14 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1576_1578delCAA	p.Gln526del	conservative_inframe_deletion	Exon 14 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	Exon 14 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-378083_172-378081delGTT		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.1579_1581delCAA	p.Gln527del	conservative_inframe_deletion	Exon 14 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2195 AN: 112113 Hom.: 38 Cov.: 21

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0427

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000738

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.0417

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0183 AC: 3341 AN: 182433 AF XY: 0.0169

Gnomad AFR exome AF: 0.00396

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.0183

Gnomad NFE exome AF: 0.0263

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0232 AC: 25343 AN: 1094572 Hom.: 242 AF XY: 0.0216 AC XY: 7813 AN XY: 361364

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

African (AFR) AF: 0.00379 AC: 100 AN: 26364

American (AMR) AF: 0.0131 AC: 461 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.0407 AC: 788 AN: 19342

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00338 AC: 183 AN: 54091

European-Finnish (FIN) AF: 0.0210 AC: 846 AN: 40372

Middle Eastern (MID) AF: 0.0389 AC: 160 AN: 4109

European-Non Finnish (NFE) AF: 0.0260 AC: 21777 AN: 838924

Other (OTH) AF: 0.0224 AC: 1028 AN: 45994

⚠️ 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 AF: 0.0196 AC: 2195 AN: 112164 Hom.: 38 Cov.: 21 AF XY: 0.0173 AC XY: 594 AN XY: 34328

African (AFR) AF: 0.00346 AC: 107 AN: 30946

American (AMR) AF: 0.0157 AC: 166 AN: 10552

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 113 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3606

South Asian (SAS) AF: 0.000740 AC: 2 AN: 2702

European-Finnish (FIN) AF: 0.0186 AC: 113 AN: 6059

Middle Eastern (MID) AF: 0.0411 AC: 9 AN: 219

European-Non Finnish (NFE) AF: 0.0288 AC: 1531 AN: 53245

Other (OTH) AF: 0.0151 AC: 23 AN: 1524

Alfa AF: 0.0280 Hom.: 226

Bravo AF: 0.0190

Asia WGS AF: 0.00438 AC: 11 AN: 2522

EpiCase AF: 0.0281

EpiControl AF: 0.0276

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (3)
-	-	2	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.3
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62653033; hg19: chrX-38147285; COSMIC: COSV58835696;