rs147649203

Variant names:

• chrX-38269751-T-C
• rs147649203
• ENST00000465127.1:c.172-396370T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-38269751-T-C
• chrX-38269751-T-G

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.2323A>G​(p.Ile775Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,207,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I775T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00020 (0 hom. 57 hem.)
• Consequence: RPGR NM_000328.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.671
• Publications: 1 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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.017639518).
• BP6: Variant X-38269751-T-C is Benign according to our data. Variant chrX-38269751-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 237687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 32 XL,AD 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.2323A>G	p.Ile775Val	missense	Exon 19 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.2320A>G	p.Ile774Val	missense	Exon 19 of 19	NP_001354174.1
	RPGR	NM_001367246.1		c.2137A>G	p.Ile713Val	missense	Exon 18 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.172-396370T>C		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2938A>G	p.Ile980Val	missense	Exon 18 of 18	ENSP00000343671.3	Q92834-1
	RPGR	ENST00000642395.2		c.2323A>G	p.Ile775Val	missense	Exon 19 of 19	ENSP00000493468.2	Q92834-2

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 32 AN: 111944 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000780

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.000191 AC: 35 AN: 183156 AF XY: 0.000177

Gnomad AFR exome AF: 0.00137

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 216 AN: 1095805 Hom.: 0 Cov.: 29 AF XY: 0.000158 AC XY: 57 AN XY: 361287

African (AFR) AF: 0.000949 AC: 25 AN: 26350

American (AMR) AF: 0.0000568 AC: 2 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30167

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40435

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.000196 AC: 165 AN: 840078

Other (OTH) AF: 0.000456 AC: 21 AN: 46013

GnomAD4 genome AF: 0.000286 AC: 32 AN: 111998 Hom.: 0 Cov.: 23 AF XY: 0.000234 AC XY: 8 AN XY: 34148

African (AFR) AF: 0.000779 AC: 24 AN: 30824

American (AMR) AF: 0.00 AC: 0 AN: 10532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

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

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53237

Other (OTH) AF: 0.00131 AC: 2 AN: 1523

Alfa AF: 0.000208 Hom.: 12

Bravo AF: 0.000419

ESP6500AA AF: 0.000783 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

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	0.069
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.93
DANN	Benign	0.46
DEOGEN2	Benign	0.036	T
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.67
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.039
Sift	Benign	0.46	T
Sift4G	Benign	0.42	T
Polyphen		0.0070	B
Vest4		0.068
MVP		0.11
ClinPred		0.0039	T
GERP RS		-2.2
Varity_R		0.061
Mutation Taster		=99/1	polymorphism

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: rs147649203; hg19: chrX-38129004;