rs771791722

Variant names:

• chrX-38275092-T-C
• rs771791722
• ENST00000465127.1:c.172-391029T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000328.3(RPGR):​c.2146A>G​(p.Lys716Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,205,545 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K716K) has been classified as Uncertain significance. The gene RPGR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 76 hem.)
• Consequence: RPGR NM_000328.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.24
• Publications: 0 publications found

Genes affected

ENSG00000250349 (HGNC:):

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

ACMG classification

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010278642).
• BP6: Variant X-38275092-T-C is Benign according to our data. Variant chrX-38275092-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 6 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000328.3. 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_000328.3		c.2146A>G	p.Lys716Glu	missense	Exon 17 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.2143A>G	p.Lys715Glu	missense	Exon 17 of 19	NP_001354174.1
	RPGR	NM_001367246.1		c.1960A>G	p.Lys654Glu	missense	Exon 16 of 18	NP_001354175.1	Q92834-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-391029T>C		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2761A>G	p.Lys921Glu	missense	Exon 16 of 18	ENSP00000343671.3	Q92834-1
	RPGR	ENST00000642395.2		c.2146A>G	p.Lys716Glu	missense	Exon 17 of 19	ENSP00000493468.2	Q92834-2

Frequencies

GnomAD3 genomes AF: 0.0000536 AC: 6 AN: 111846 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00226

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000224 AC: 41 AN: 183001 AF XY: 0.000355

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: 0.000119 AC: 130 AN: 1093646 Hom.: 0 Cov.: 28 AF XY: 0.000212 AC XY: 76 AN XY: 359310

African (AFR) AF: 0.00 AC: 0 AN: 26316

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19347

East Asian (EAS) AF: 0.00 AC: 0 AN: 30159

South Asian (SAS) AF: 0.00235 AC: 127 AN: 54009

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4102

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 838174

Other (OTH) AF: 0.0000435 AC: 2 AN: 45937

GnomAD4 genome AF: 0.0000536 AC: 6 AN: 111899 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34071

African (AFR) AF: 0.00 AC: 0 AN: 30819

American (AMR) AF: 0.00 AC: 0 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3586

South Asian (SAS) AF: 0.00226 AC: 6 AN: 2651

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53168

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.000115 Hom.: 2

Bravo AF: 0.0000113

ExAC AF: 0.000362 AC: 44

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.2
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.15
Sift	Benign	0.39	T
Sift4G	Benign	0.43	T
Polyphen		1.0	D
Vest4		0.38
MutPred		0.20		Loss of ubiquitination at K716 (P = 9e-04)
MVP		0.44
ClinPred		0.10	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs771791722; hg19: chrX-38134345;