rs41312104

Variant names:

• chrX-38288016-G-A
• rs41312104
• NM_001034853.2:c.1598C>T

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.1598C>T​(p.Thr533Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,207,527 control chromosomes in the GnomAD database, including 288 homozygotes. There are 8,907 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T533A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.020 (38 hom., 621 hem., cov: 22)
  • Exomes 𝑓: 0.024 (250 hom. 8286 hem.)
• Consequence: RPGR NM_001034853.2 missense
• Clinical Significance: Benign reviewed by expert panel B:10 O:1
• Conservation: PhyloP100: -0.0500
• Publications: 7 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=0.0017929971).
• BP6: Variant X-38288016-G-A is Benign according to our data. Variant chrX-38288016-G-A is described in ClinVar as Benign. ClinVar VariationId is 92854.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0199 (2225/111643) while in subpopulation NFE AF = 0.029 (1540/53134). AF 95% confidence interval is 0.0278. There are 38 homozygotes in GnomAd4. There are 621 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2225 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.1598C>T	p.Thr533Met	missense	Exon 14 of 15	NP_001030025.1	Q92834-6
	RPGR	NM_000328.3		c.1598C>T	p.Thr533Met	missense	Exon 14 of 19	NP_000319.1	Q92834-2
	RPGR	NM_001367245.1		c.1595C>T	p.Thr532Met	missense	Exon 14 of 19	NP_001354174.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPGR	ENST00000645032.1	MANE Select	c.1598C>T	p.Thr533Met	missense	Exon 14 of 15	ENSP00000495537.1	Q92834-6
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-378105G>A		intron	N/A	ENSP00000417050.1	B4E171
	RPGR	ENST00000339363.7	TSL:5	c.1598C>T	p.Thr533Met	missense	Exon 14 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 2225 AN: 111591 Hom.: 38 Cov.: 22

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0439

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0420

Gnomad NFE AF: 0.0290

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0189 AC: 3446 AN: 182733 AF XY: 0.0182

Gnomad AFR exome AF: 0.00411

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.0196

Gnomad NFE exome AF: 0.0272

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0238 AC: 26108 AN: 1095884 Hom.: 250 Cov.: 30 AF XY: 0.0229 AC XY: 8286 AN XY: 362224

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00379 AC: 100 AN: 26368

American (AMR) AF: 0.0132 AC: 465 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 794 AN: 19349

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30194

South Asian (SAS) AF: 0.00346 AC: 187 AN: 54108

European-Finnish (FIN) AF: 0.0214 AC: 864 AN: 40422

Middle Eastern (MID) AF: 0.0396 AC: 163 AN: 4120

European-Non Finnish (NFE) AF: 0.0268 AC: 22482 AN: 840105

Other (OTH) AF: 0.0229 AC: 1052 AN: 46028

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0199 AC: 2225 AN: 111643 Hom.: 38 Cov.: 22 AF XY: 0.0183 AC XY: 621 AN XY: 33895

African (AFR) AF: 0.00364 AC: 112 AN: 30783

American (AMR) AF: 0.0160 AC: 168 AN: 10497

Ashkenazi Jewish (ASJ) AF: 0.0439 AC: 116 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00150 AC: 4 AN: 2663

European-Finnish (FIN) AF: 0.0192 AC: 114 AN: 5927

Middle Eastern (MID) AF: 0.0413 AC: 9 AN: 218

European-Non Finnish (NFE) AF: 0.0290 AC: 1540 AN: 53134

Other (OTH) AF: 0.0151 AC: 23 AN: 1525

Alfa AF: 0.0263 Hom.: 1230

Bravo AF: 0.0190

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0322 AC: 93

ESP6500AA AF: 0.00339 AC: 13

ESP6500EA AF: 0.0293 AC: 197

ExAC AF: 0.0195 AC: 2362

EpiCase AF: 0.0281

EpiControl AF: 0.0287

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (4)
-	-	2	Primary ciliary dyskinesia (2)
-	-	1	RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.015
DANN	Benign	0.78
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.79	N
PhyloP100		-0.050
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.015
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Polyphen		0.27	B
Vest4		0.061
MPC		0.022
ClinPred		0.0098	T
GERP RS		-3.7
Varity_R		0.012
gMVP		0.061
Mutation Taster		=99/1	polymorphism (auto)

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: rs41312104; hg19: chrX-38147269;