Genetic Variant RPGR:p.Gly816_Glu820del (chrX-38286537-TCCTCTACTTCCCCTC-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBS1BS2

The NM_001034853.2(RPGR):c.2447_2461delGAGGGGAAGTAGAGG(p.Gly816_Glu820del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 896,827 control chromosomes in the GnomAD database, including 7 homozygotes. There are 907 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., 0 hem., cov: 4)

Exomes 𝑓: 0.0035 ( 7 hom. 907 hem. )

Consequence

RPGR
NM_001034853.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: 1.59

Publications

2 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 -14 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001034853.2.

BP6

Variant X-38286537-TCCTCTACTTCCCCTC-T is Benign according to our data. Variant chrX-38286537-TCCTCTACTTCCCCTC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 414015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00354 (3064/864447) while in subpopulation NFE AF = 0.0041 (2835/691275). AF 95% confidence interval is 0.00397. There are 7 homozygotes in GnomAdExome4. There are 907 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

BS2

High AC in GnomAd4 at 58 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.2447_2461delGAGGGGAAGTAGAGG	p.Gly816_Glu820del	disruptive_inframe_deletion	Exon 15 of 15	NP_001030025.1	Q92834-6
RPGR	NM_000328.3		c.1905+542_1905+556delGAGGGGAAGTAGAGG		intron	N/A	NP_000319.1	Q92834-2
RPGR	NM_001367245.1		c.1902+542_1902+556delGAGGGGAAGTAGAGG		intron	N/A	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPGR	ENST00000645032.1	MANE Select	c.2447_2461delGAGGGGAAGTAGAGG	p.Gly816_Glu820del	disruptive_inframe_deletion	Exon 15 of 15	ENSP00000495537.1	Q92834-6
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-379564_172-379550delTACTTCCCCTCCCTC		intron	N/A	ENSP00000417050.1	B4E171
RPGR	ENST00000339363.7	TSL:5	c.2520+542_2520+556delGAGGGGAAGTAGAGG		intron	N/A	ENSP00000343671.3	Q92834-1

Frequencies

GnomAD3 genomes

AF:

0.00179

AC:

AN:

32387

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00334

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00216

Gnomad OTH

AF:

0.00266

GnomAD2 exomes

AF:

0.00114

AC:

105

AN:

91821

AF XY:

0.000651

show subpopulations

Gnomad AFR exome

AF:

0.00156

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.000271

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.000749

GnomAD4 exome

AF:

0.00354

AC:

3064

AN:

864447

Hom.:

AF XY:

0.00347

AC XY:

907

AN XY:

261387

show subpopulations

African (AFR)

AF:

0.00202

AC:

AN:

19270

American (AMR)

AF:

0.000920

AC:

AN:

21739

Ashkenazi Jewish (ASJ)

AF:

0.00122

AC:

AN:

12322

East Asian (EAS)

AF:

0.00108

AC:

AN:

14796

South Asian (SAS)

AF:

0.000787

AC:

AN:

43186

European-Finnish (FIN)

AF:

0.000448

AC:

AN:

26767

Middle Eastern (MID)

AF:

0.000496

AC:

AN:

2016

European-Non Finnish (NFE)

AF:

0.00410

AC:

2835

AN:

691275

Other (OTH)

AF:

0.00278

AC:

AN:

33076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.427

Heterozygous variant carriers

172

258

344

430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

118

236

354

472

590

<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:

0.00179

AC:

AN:

32380

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

2000

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

7616

American (AMR)

AF:

0.00164

AC:

AN:

2437

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

888

East Asian (EAS)

AF:

0.00

AC:

AN:

955

South Asian (SAS)

AF:

0.00341

AC:

AN:

293

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00216

AC:

AN:

18046

Other (OTH)

AF:

0.00260

AC:

AN:

384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00115

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia (1)

X-linked cone-rod dystrophy 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=165/35

polymorphism

(source)

Splicing

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