Genetic Variant RPGR:p.Gly854_Glu855insGluGlyGluGluGluGluGly (chrX-38286437-T-TCCTTCCTCCTCTTCCCCCTCC) – 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.2541_2561dupGGAGGGGGAAGAGGAGGAAGG(p.Gly854_Glu855insGluGlyGluGluGluGluGly) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 839,424 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.0 ( 0 hom., 0 hem., cov: 5)

Exomes 𝑓: 0.00016 ( 0 hom. 35 hem. )

Failed GnomAD Quality Control

Consequence

RPGR
NM_001034853.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -2.19

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)
RPGR-related retinopathy
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
primary ciliary dyskinesia-retinitis pigmentosa syndrome
Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
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-38286437-T-TCCTTCCTCCTCTTCCCCCTCC is Benign according to our data. Variant chrX-38286437-T-TCCTTCCTCCTCTTCCCCCTCC is described in ClinVar as Likely_benign. ClinVar VariationId is 257194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000163 (137/839424) while in subpopulation EAS AF = 0.00372 (67/18033). AF 95% confidence interval is 0.003. There are 0 homozygotes in GnomAdExome4. There are 35 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 137 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
RPGR	NM_001034853.2	MANE Select	c.2541_2561dupGGAGGGGGAAGAGGAGGAAGG	p.Gly854_Glu855insGluGlyGluGluGluGluGly	disruptive_inframe_insertion	Exon 15 of 15	NP_001030025.1
RPGR	NM_000328.3		c.1905+636_1905+656dupGGAGGGGGAAGAGGAGGAAGG		intron	N/A	NP_000319.1
RPGR	NM_001367245.1		c.1902+636_1902+656dupGGAGGGGGAAGAGGAGGAAGG		intron	N/A	NP_001354174.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPGR	ENST00000645032.1	MANE Select	c.2541_2561dupGGAGGGGGAAGAGGAGGAAGG	p.Gly854_Glu855insGluGlyGluGluGluGluGly	disruptive_inframe_insertion	Exon 15 of 15	ENSP00000495537.1
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-379642_172-379622dupCCCTTCCTCCTCTTCCCCCTC		intron	N/A	ENSP00000417050.1
RPGR	ENST00000339363.7	TSL:5	c.2520+636_2520+656dupGGAGGGGGAAGAGGAGGAAGG		intron	N/A	ENSP00000343671.3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

18070

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

50113

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000163

AC:

137

AN:

839424

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

237228

show subpopulations

African (AFR)

AF:

0.000273

AC:

AN:

18340

American (AMR)

AF:

0.00274

AC:

AN:

15714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11397

East Asian (EAS)

AF:

0.00372

AC:

AN:

18033

South Asian (SAS)

AF:

0.0000308

AC:

AN:

32455

European-Finnish (FIN)

AF:

0.0000393

AC:

AN:

25413

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1984

European-Non Finnish (NFE)

AF:

0.0000176

AC:

AN:

682549

Other (OTH)

AF:

0.000239

AC:

AN:

33539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

18082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

1072

African (AFR)

AF:

0.00

AC:

AN:

3724

American (AMR)

AF:

0.00

AC:

AN:

1371

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

515

East Asian (EAS)

AF:

0.00

AC:

AN:

612

South Asian (SAS)

AF:

0.00

AC:

AN:

174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

978

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

10303

Other (OTH)

AF:

0.00

AC:

AN:

255

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Primary ciliary dyskinesia

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.2

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-38286437-TCCTTCCTCCTCTTCCCCCTCCCCTTCCTCCTCTTCCCCCTCC-TCCTTCCTCCTCTTCCCCCTCCCCTTCCTCCTCTTCCCCCTCCCCTTCCTCCTCTTCCCCCTCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over