rs121908449

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3_StrongPP5_Moderate

The NM_003835.4(RGS9):c.895T>C(p.Trp299Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

RGS9
NM_003835.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:4O:1

Conservation

PhyloP100: 7.81

Publications

11 publications found

Variant links:

Genes affected

RGS9 (HGNC:10004): (regulator of G protein signaling 9) This gene encodes a member of the RGS family of GTPase activating proteins that function in various signaling pathways by accelerating the deactivation of G proteins. This protein is anchored to photoreceptor membranes in retinal cells and deactivates G proteins in the rod and cone phototransduction cascades. Mutations in this gene result in bradyopsia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

RGS9 Gene-Disease associations (from GenCC):

prolonged electroretinal response suppression 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
bradyopsia
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia

RGS9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 17-65197160-T-C is Pathogenic according to our data. Variant chr17-65197160-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5862.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS9	NM_003835.4 link	c.895T>C	p.Trp299Arg	missense_variant	Exon 13 of 19	ENST00000262406.10	NP_003826.2	O75916-1A8K1G1
RGS9	NM_001081955.3 link	c.886T>C	p.Trp296Arg	missense_variant	Exon 13 of 19		NP_001075424.1	O75916-5
RGS9	NM_001165933.2 link	c.886T>C	p.Trp296Arg	missense_variant	Exon 13 of 17		NP_001159405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS9	ENST00000262406.10 link	c.895T>C	p.Trp299Arg	missense_variant	Exon 13 of 19	1	NM_003835.4	ENSP00000262406.9		O75916-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000120

AC:

AN:

249106

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.0000647

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:

0.000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000276

AC:

403

AN:

1461602

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000352

AC:

391

AN:

1111846

Other (OTH)

AF:

0.000166

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000184

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41428

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68048

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000329

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.000124

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 299 of the RGS9 protein (p.Trp299Arg). This variant is present in population databases (rs121908449, gnomAD 0.02%). This missense change has been observed in individuals with bradyopsia and/or cone dysfunction (PMID: 14702087, 17826834, 19818506). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5862). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RGS9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RGS9 function (PMID: 14702087). For these reasons, this variant has been classified as Pathogenic. -

Leber congenital amaurosis

Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Bradyopsia

Other:1

Jan 01, 2004

OMIM

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

0.97

DEOGEN2

Uncertain

0.50

D;.;.;D

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Uncertain

0.053

MutationAssessor

Pathogenic

4.2

.;.;.;H

PhyloP100

7.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-13

.;.;D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

.;.;D;D

Sift4G

Pathogenic

0.0010

.;D;D;D

Polyphen

1.0

.;.;D;D

Vest4

0.99, 0.99, 0.96

MutPred

0.95

Gain of methylation at W299 (P = 0.0335);.;.;Gain of methylation at W299 (P = 0.0335);

MVP

0.87

MPC

1.0

ClinPred

1.0

GERP RS

5.3

Varity_R

0.95

gMVP

0.92

Mutation Taster

=1/99

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over