chrX-38286437-TCCTTCCTCCTCTTCCCCCTCCCCTTCCTCCTCTTCCCCCTCC-T

Variant names:

• chrX-38286437-TCCTTCCTCCTCTTCCCCCTCCCCTTCCTCCTCTTCCCCCTCC-T
• rs751710678
• NM_001034853.2:c.2520_2561delGGAGGGGGAAGAGGAGGAAGGGGAGGGGGAAGAGGAGGAAGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001034853.2(RPGR):​c.2520_2561delGGAGGGGGAAGAGGAGGAAGGGGAGGGGGAAGAGGAGGAAGG​(p.Glu841_Gly854del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000119 in 839,435 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G840G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 3)
  • Exomes 𝑓: 0.0000012 (0 hom. 0 hem.)
• Consequence: RPGR NM_001034853.2 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0290
• Publications: 0 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)
• RPGR-related retinopathy

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

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001034853.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2	c.2520_2561delGGAGGGGGAAGAGGAGGAAGGGGAGGGGGAAGAGGAGGAAGG	p.Glu841_Gly854del	disruptive_inframe_deletion	Exon 15 of 15	ENST00000645032.1	NP_001030025.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1	c.2520_2561delGGAGGGGGAAGAGGAGGAAGGGGAGGGGGAAGAGGAGGAAGG	p.Glu841_Gly854del	disruptive_inframe_deletion	Exon 15 of 15		NM_001034853.2	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	c.172-379663_172-379622delCCCTTCCTCCTCTTCCCCCTCCCCTTCCTCCTCTTCCCCCTC		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD2 exomes AF: 0.00 AC: 0 AN: 50113 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000119 AC: 1 AN: 839435 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 237221

African (AFR) AF: 0.00 AC: 0 AN: 18340

American (AMR) AF: 0.00 AC: 0 AN: 15729

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11397

East Asian (EAS) AF: 0.00 AC: 0 AN: 18044

South Asian (SAS) AF: 0.00 AC: 0 AN: 32453

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25413

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1984

European-Non Finnish (NFE) AF: 0.00000147 AC: 1 AN: 682534

Other (OTH) AF: 0.00 AC: 0 AN: 33541

GnomAD4 genome Cov.: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Feb 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.2520_2561del, results in the deletion of 14 amino acid(s) of the RPGR (ORF15) protein (p.Glu843_Gly856del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RPGR (ORF15)-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.029

Splicing

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

Other links and lift over

dbSNP: rs751710678; hg19: chrX-38145690;