Genetic Variant RPGR:p.Gln467Lys (chrX-38297299-G-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.1399C>A(p.Gln467Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,208,092 control chromosomes in the GnomAD database, including 1 homozygotes. There are 71 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., 23 hem., cov: 22)

Exomes 𝑓: 0.00016 ( 1 hom. 48 hem. )

Consequence

RPGR
NM_001034853.2 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -0.753

Publications

0 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

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007265836).

BP6

Variant X-38297299-G-T is Benign according to our data. Variant chrX-38297299-G-T is described in ClinVar as Benign. ClinVar VariationId is 414012.Status of the report is reviewed_by_expert_panel, 3 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000452 (50/110560) while in subpopulation AMR AF = 0.0038 (39/10263). AF 95% confidence interval is 0.00286. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAd4 at 50 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	NM_001034853.2	MANE Select	c.1399C>A	p.Gln467Lys	missense	Exon 11 of 15	NP_001030025.1	Q92834-6
RPGR	NM_000328.3		c.1399C>A	p.Gln467Lys	missense	Exon 11 of 19	NP_000319.1	Q92834-2
RPGR	NM_001367245.1		c.1396C>A	p.Gln466Lys	missense	Exon 11 of 19	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	ENST00000645032.1	MANE Select	c.1399C>A	p.Gln467Lys	missense	Exon 11 of 15	ENSP00000495537.1	Q92834-6
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-368822G>T		intron	N/A	ENSP00000417050.1	B4E171
RPGR	ENST00000339363.7	TSL:5	c.1399C>A	p.Gln467Lys	missense	Exon 11 of 18	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes

AF:

0.000452

AC:

AN:

110507

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000659

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

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:

0.000132

Gnomad OTH

AF:

0.00135

GnomAD2 exomes

AF:

0.000387

AC:

AN:

183340

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000611

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000165

AC:

181

AN:

1097532

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

362926

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26387

American (AMR)

AF:

0.00213

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30173

South Asian (SAS)

AF:

0.00

AC:

AN:

54133

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40511

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

841548

Other (OTH)

AF:

0.000217

AC:

AN:

46069

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000452

AC:

AN:

110560

Hom.:

Cov.:

AF XY:

0.000702

AC XY:

AN XY:

32764

show subpopulations

African (AFR)

AF:

0.0000657

AC:

AN:

30422

American (AMR)

AF:

0.00380

AC:

AN:

10263

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3492

South Asian (SAS)

AF:

0.00

AC:

AN:

2572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5755

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

53011

Other (OTH)

AF:

0.00133

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000102

Hom.:

Bravo

AF:

0.000518

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000157

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

RPGR-related disorder (1)

RPGR-related retinopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.10

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.030

FATHMM_MKL

Benign

0.0066

LIST_S2

Benign

0.35

M_CAP

Benign

0.0081

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

-0.75

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.80

REVEL

Benign

0.013

Sift

Benign

0.39

Sift4G

Benign

0.55

Polyphen

0.021

Vest4

0.070

MutPred

0.29

Gain of ubiquitination at Q467 (P = 0.001)

MVP

0.19

MPC

0.025

ClinPred

0.0052

GERP RS

-4.1

Varity_R

0.10

gMVP

0.12

Mutation Taster

=98/2

polymorphism

(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