NM_001034853.2:c.2223G>C

Variant names:

• chrX-38286776-C-G
• rs147619484
• NM_001034853.2:c.2223G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001034853.2(RPGR):​c.2223G>C​(p.Glu741Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000095 in 1,052,754 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E741E) has been classified as Benign. The gene RPGR is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27
• Publications: 4 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

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05919814).

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.2223G>C	p.Glu741Asp	missense	Exon 15 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1905+318G>C		intron	N/A	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1902+318G>C		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.2223G>C	p.Glu741Asp	missense	Exon 15 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-379345C>G		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.2520+318G>C		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 9.50e-7 AC: 1 AN: 1052754 Hom.: 0 Cov.: 34 AF XY: 0.00000291 AC XY: 1 AN XY: 343544

African (AFR) AF: 0.00 AC: 0 AN: 24921

American (AMR) AF: 0.00 AC: 0 AN: 27895

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18526

East Asian (EAS) AF: 0.00 AC: 0 AN: 27200

South Asian (SAS) AF: 0.00 AC: 0 AN: 49619

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3561

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 819119

Other (OTH) AF: 0.0000225 AC: 1 AN: 44365

GnomAD4 genome Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	2.0
DANN	Benign	0.43
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.93	T
PhyloP100		-2.3
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.016
Sift4G	Benign	0.33	T
Vest4		0.13
MutPred		0.30		Loss of helix (P = 0.4763)
MVP		0.18
MPC		0.71
ClinPred		0.10	T
GERP RS		-2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.0053
Mutation Taster		=97/3	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: rs147619484; hg19: chrX-38146029;