chr17-65193569-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003835.4(RGS9):c.773C>T(p.Ser258Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00515 in 1,613,216 control chromosomes in the GnomAD database, including 138 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 124 hom. )

Consequence

RGS9
NM_003835.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.773

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018083751).

BP6

Variant 17-65193569-C-T is Benign according to our data. Variant chr17-65193569-C-T is described in ClinVar as Benign. ClinVar VariationId is 167593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00505 (769/152292) while in subpopulation EAS AF = 0.0338 (175/5178). AF 95% confidence interval is 0.0297. There are 14 homozygotes in GnomAd4. There are 446 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS9	NM_003835.4 link	c.773C>T	p.Ser258Leu	missense_variant	Exon 12 of 19	ENST00000262406.10	NP_003826.2	O75916-1A8K1G1
RGS9	NM_001081955.3 link	c.764C>T	p.Ser255Leu	missense_variant	Exon 12 of 19		NP_001075424.1	O75916-5
RGS9	NM_001165933.2 link	c.764C>T	p.Ser255Leu	missense_variant	Exon 12 of 17		NP_001159405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS9	ENST00000262406.10 link	c.773C>T	p.Ser258Leu	missense_variant	Exon 12 of 19	1	NM_003835.4	ENSP00000262406.9		O75916-1

Frequencies

GnomAD3 genomes

AF:

0.00497

AC:

757

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.00837

Gnomad EAS

AF:

0.0337

Gnomad SAS

AF:

0.0331

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00213

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00928

AC:

2316

AN:

249562

AF XY:

0.0105

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.0270

Gnomad FIN exome

AF:

0.00955

Gnomad NFE exome

AF:

0.00241

Gnomad OTH exome

AF:

0.0112

GnomAD4 exome

AF:

0.00516

AC:

7543

AN:

1460924

Hom.:

124

Cov.:

AF XY:

0.00601

AC XY:

4366

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33468

American (AMR)

AF:

0.00411

AC:

184

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00777

AC:

203

AN:

26122

East Asian (EAS)

AF:

0.0402

AC:

1597

AN:

39684

South Asian (SAS)

AF:

0.0342

AC:

2948

AN:

86218

European-Finnish (FIN)

AF:

0.00917

AC:

490

AN:

53420

Middle Eastern (MID)

AF:

0.0208

AC:

120

AN:

5764

European-Non Finnish (NFE)

AF:

0.00138

AC:

1535

AN:

1111166

Other (OTH)

AF:

0.00747

AC:

451

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

379

758

1138

1517

1896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.00505

AC:

769

AN:

152292

Hom.:

Cov.:

AF XY:

0.00599

AC XY:

446

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41558

American (AMR)

AF:

0.00686

AC:

105

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00837

AC:

AN:

3466

East Asian (EAS)

AF:

0.0338

AC:

175

AN:

5178

South Asian (SAS)

AF:

0.0330

AC:

159

AN:

4824

European-Finnish (FIN)

AF:

0.0106

AC:

112

AN:

10610

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00213

AC:

145

AN:

68036

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00402

Hom.:

Bravo

AF:

0.00369

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000739

AC:

ESP6500EA

AF:

0.00155

AC:

ExAC

AF:

0.00951

AC:

1150

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00338

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.70

CADD

Benign

4.1

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.022

T;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.74

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.24

.;.;.;N

PhyloP100

-0.77

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

.;.;N;N

REVEL

Benign

0.0080

Sift

Benign

0.53

.;.;T;T

Sift4G

Benign

0.36

.;T;T;T

Polyphen

0.0040, 0.0050

.;.;B;B

Vest4

0.14, 0.13, 0.14

MVP

0.30

MPC

0.16

ClinPred

0.0023

GERP RS

-2.4

Varity_R

0.067

gMVP

0.41

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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