dbSNP rs62638654: RPGR:p.Lys244Lys (chrX-38310661-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001034853.2(RPGR):c.732G>A(p.Lys244Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,209,422 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,062 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene RPGR is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., 47 hem., cov: 23)

Exomes 𝑓: 0.0027 ( 6 hom. 1015 hem. )

Consequence

RPGR
NM_001034853.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6O:1

Conservation

PhyloP100: -1.22

Publications

1 publications found

Variant links:

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

RPGR links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

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

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant X-38310661-C-T is Benign according to our data. Variant chrX-38310661-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 98797.

BP7

Synonymous conserved (PhyloP=-1.22 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00188 (209/111397) while in subpopulation NFE AF = 0.0032 (170/53083). AF 95% confidence interval is 0.00281. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 209 AD,XL 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	NM_001034853.2	MANE Select	c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 15	NP_001030025.1	Q92834-6
RPGR	NM_000328.3		c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 19	NP_000319.1	Q92834-2
RPGR	NM_001367245.1		c.729G>A	p.Lys243Lys	synonymous	Exon 7 of 19	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	ENST00000645032.1	MANE Select	c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 15	ENSP00000495537.1	Q92834-6
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-355460C>T		intron	N/A	ENSP00000417050.1	B4E171
RPGR	ENST00000339363.7	TSL:5	c.732G>A	p.Lys244Lys	synonymous	Exon 7 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

211

AN:

111346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000556

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000954

Gnomad ASJ

AF:

0.000759

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000383

Gnomad FIN

AF:

0.000667

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.00320

Gnomad OTH

AF:

0.00269

GnomAD2 exomes

AF:

0.00196

AC:

360

AN:

183209

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.000380

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00100

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00273

AC:

2996

AN:

1098025

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

1015

AN XY:

363399

show subpopulations

African (AFR)

AF:

0.000379

AC:

AN:

26395

American (AMR)

AF:

0.00136

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.000980

AC:

AN:

19383

East Asian (EAS)

AF:

0.00

AC:

AN:

30197

South Asian (SAS)

AF:

0.00140

AC:

AN:

54125

European-Finnish (FIN)

AF:

0.000814

AC:

AN:

40516

Middle Eastern (MID)

AF:

0.00823

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00313

AC:

2639

AN:

841992

Other (OTH)

AF:

0.00297

AC:

137

AN:

46089

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

112

224

335

447

559

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00188

AC:

209

AN:

111397

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

AN XY:

33587

show subpopulations

African (AFR)

AF:

0.000555

AC:

AN:

30632

American (AMR)

AF:

0.000953

AC:

AN:

10492

Ashkenazi Jewish (ASJ)

AF:

0.000759

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3548

South Asian (SAS)

AF:

0.000384

AC:

AN:

2604

European-Finnish (FIN)

AF:

0.000667

AC:

AN:

5993

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00320

AC:

170

AN:

53083

Other (OTH)

AF:

0.00265

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.00198

EpiCase

AF:

0.00464

EpiControl

AF:

0.00415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (3)

Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

1.4

(source)

DANN

Benign

0.64

PhyloP100

-1.2

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over