rs113968324

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000465127.1(ENSG00000250349):c.172-396412C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000746 in 1,206,513 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000064 ( 0 hom. 3 hem. )

Consequence

ENSG00000250349
ENST00000465127.1 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.01

Publications

1 publications found

Variant links:

Genes affected

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.113357574).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
RPGR	NM_000328.3 link	c.2365G>C	p.Asp789His	missense_variant	Exon 19 of 19	NP_000319.1	Q92834-2
RPGR	NM_001367245.1 link	c.2362G>C	p.Asp788His	missense_variant	Exon 19 of 19	NP_001354174.1
RPGR	NM_001367246.1 link	c.2179G>C	p.Asp727His	missense_variant	Exon 18 of 18	NP_001354175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000250349	ENST00000465127.1 link	c.172-396412C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111172

Hom.:

Cov.:

show subpopulations

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:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000639

AC:

AN:

1095341

Hom.:

Cov.:

AF XY:

0.00000831

AC XY:

AN XY:

360817

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26356

American (AMR)

AF:

0.00

AC:

AN:

35201

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19363

East Asian (EAS)

AF:

0.00

AC:

AN:

30164

South Asian (SAS)

AF:

0.00

AC:

AN:

54065

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40483

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.00000834

AC:

AN:

839595

Other (OTH)

AF:

0.00

AC:

AN:

45988

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000281198), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.338

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:

0.0000180

AC:

AN:

111172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33388

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30584

American (AMR)

AF:

0.00

AC:

AN:

10451

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3568

South Asian (SAS)

AF:

0.00

AC:

AN:

2644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5827

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000377

AC:

AN:

53053

Other (OTH)

AF:

0.00

AC:

AN:

1491

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Aug 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2365G>C (p.D789H) alteration is located in exon 19 (coding exon 19) of the RPGR gene. This alteration results from a G to C substitution at nucleotide position 2365, causing the aspartic acid (D) at amino acid position 789 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.86

CADD

Benign

7.9

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.035

.;.;T;.;.

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.45

.;T;T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;.;N;.;.

PhyloP100

1.0

PROVEAN

Benign

-1.2

N;.;N;.;.

REVEL

Benign

0.11

Sift

Benign

0.043

D;.;D;.;.

Sift4G

Uncertain

0.034

D;.;D;.;.

Polyphen

0.85

P;P;.;.;.

Vest4

0.092

MutPred

0.15

Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);.;.;.;

MVP

0.068

ClinPred

0.25

GERP RS

1.2

Varity_R

0.084

Mutation Taster

=94/6

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

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

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