NM_001034853.2:c.1033A>G

Variant names:

• chrX-38301273-T-C
• rs41305223
• NM_001034853.2:c.1033A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001034853.2(RPGR):​c.1033A>G​(p.Asn345Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,203,141 control chromosomes in the GnomAD database, including 51 homozygotes. There are 3,751 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (2 hom., 204 hem., cov: 22)
  • Exomes 𝑓: 0.010 (49 hom. 3547 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:6 O:1
• Conservation: PhyloP100: 0.789
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0090559125).
• BP6: Variant X-38301273-T-C is Benign according to our data. Variant chrX-38301273-T-C is described in ClinVar as Benign. ClinVar VariationId is 98725.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00709 (790/111478) while in subpopulation NFE AF = 0.0117 (622/53079). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 790 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.1033A>G	p.Asn345Asp	missense	Exon 9 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1033A>G	p.Asn345Asp	missense	Exon 9 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1030A>G	p.Asn344Asp	missense	Exon 9 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1033A>G	p.Asn345Asp	missense	Exon 9 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-364848T>C		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000494841.1	TSL:1	n.296A>G		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 791 AN: 111428 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00325

Gnomad ASJ AF: 0.00228

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00667

GnomAD2 exomes AF: 0.00706 AC: 1268 AN: 179715 AF XY: 0.00660

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00270

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.00920

GnomAD4 exome AF: 0.0104 AC: 11320 AN: 1091663 Hom.: 49 Cov.: 27 AF XY: 0.00992 AC XY: 3547 AN XY: 357487

African (AFR) AF: 0.000875 AC: 23 AN: 26282

American (AMR) AF: 0.00310 AC: 109 AN: 35151

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 56 AN: 19341

East Asian (EAS) AF: 0.00 AC: 0 AN: 30115

South Asian (SAS) AF: 0.00195 AC: 105 AN: 53759

European-Finnish (FIN) AF: 0.00742 AC: 300 AN: 40432

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4116

European-Non Finnish (NFE) AF: 0.0124 AC: 10345 AN: 836603

Other (OTH) AF: 0.00822 AC: 377 AN: 45864

GnomAD4 genome AF: 0.00709 AC: 790 AN: 111478 Hom.: 2 Cov.: 22 AF XY: 0.00605 AC XY: 204 AN XY: 33718

African (AFR) AF: 0.00225 AC: 69 AN: 30686

American (AMR) AF: 0.00325 AC: 34 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00228 AC: 6 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00151 AC: 4 AN: 2650

European-Finnish (FIN) AF: 0.00754 AC: 45 AN: 5972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0117 AC: 622 AN: 53079

Other (OTH) AF: 0.00658 AC: 10 AN: 1519

Alfa AF: 0.00982 Hom.: 487

Bravo AF: 0.00635

TwinsUK AF: 0.0135 AC: 50

ALSPAC AF: 0.0145 AC: 42

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.0109 AC: 73

ExAC AF: 0.00760 AC: 922

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	not specified (1)
-	-	1	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.7
DANN	Benign	0.89
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.79
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.24
Sift	Benign	0.34	T
Sift4G	Benign	0.40	T
Polyphen		0.020	B
Vest4		0.12
MVP		0.64
MPC		1.1
ClinPred		0.013	T
GERP RS		-3.1
PromoterAI		0.013	Neutral
Varity_R		0.25
gMVP		0.76
Mutation Taster		=96/4	polymorphism (auto)

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: rs41305223; hg19: chrX-38160526; COSMIC: COSV58834282; COSMIC: COSV58834282;