NM_001034853.2:c.222C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001034853.2(RPGR):c.222C>T(p.Ala74Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,208,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 251 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., 16 hem., cov: 23)

Exomes 𝑓: 0.00061 ( 0 hom. 235 hem. )

Consequence

RPGR
NM_001034853.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.790

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)
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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant X-38322878-G-A is Benign according to our data. Variant chrX-38322878-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 454515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.79 with no splicing effect.

BS2

High AC in GnomAd4 at 51 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPGR	NM_001034853.2 link	c.222C>T	p.Ala74Ala	synonymous_variant	Exon 3 of 15	ENST00000645032.1	NP_001030025.1	Q92834-6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPGR	ENST00000645032.1 link	c.222C>T	p.Ala74Ala	synonymous_variant	Exon 3 of 15		NM_001034853.2	ENSP00000495537.1		Q92834-6
ENSG00000250349	ENST00000465127.1 link	c.172-343243G>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.000455

AC:

AN:

112016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000948

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000365

Gnomad FIN

AF:

0.000665

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000771

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000665

AC:

122

AN:

183463

AF XY:

0.000663

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000292

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000625

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.000615

AC:

674

AN:

1096354

Hom.:

Cov.:

AF XY:

0.000649

AC XY:

235

AN XY:

361920

show subpopulations

African (AFR)

AF:

0.0000759

AC:

AN:

26352

American (AMR)

AF:

0.000341

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19357

East Asian (EAS)

AF:

0.00

AC:

AN:

30128

South Asian (SAS)

AF:

0.000647

AC:

AN:

54098

European-Finnish (FIN)

AF:

0.000592

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00194

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.000654

AC:

550

AN:

840528

Other (OTH)

AF:

0.000891

AC:

AN:

46033

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000455

AC:

AN:

112016

Hom.:

Cov.:

AF XY:

0.000468

AC XY:

AN XY:

34186

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30844

American (AMR)

AF:

0.0000948

AC:

AN:

10550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3601

South Asian (SAS)

AF:

0.000365

AC:

AN:

2742

European-Finnish (FIN)

AF:

0.000665

AC:

AN:

6016

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000771

AC:

AN:

53175

Other (OTH)

AF:

0.00

AC:

AN:

1518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000477

Hom.:

Bravo

AF:

0.000306

EpiCase

AF:

0.000491

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 08, 2015

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 20, 2018

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.18

(source)

DANN

Benign

0.29

PhyloP100

-0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over