rs121908449

Variant names:

• chr17-65197160-T-C
• rs121908449
• NM_003835.4:c.895T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:4 O:1
• Conservation: PhyloP100: 7.81
• Publications: 11 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003835.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS9	NM_003835.4	MANE Select	c.895T>C	p.Trp299Arg	missense	Exon 13 of 19	NP_003826.2	O75916-1
	RGS9	NM_001081955.3		c.886T>C	p.Trp296Arg	missense	Exon 13 of 19	NP_001075424.1	O75916-5
	RGS9	NM_001165933.2		c.886T>C	p.Trp296Arg	missense	Exon 13 of 17	NP_001159405.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS9	ENST00000262406.10	TSL:1 MANE Select	c.895T>C	p.Trp299Arg	missense	Exon 13 of 19	ENSP00000262406.9	O75916-1
	RGS9	ENST00000449996.7	TSL:1	c.886T>C	p.Trp296Arg	missense	Exon 13 of 19	ENSP00000396329.3	O75916-5
	RGS9	ENST00000443584.7	TSL:1	c.886T>C	p.Trp296Arg	missense	Exon 13 of 18	ENSP00000405814.3	E9PD91

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152200 Hom.: 0 Cov.: 32

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: 30 AN: 249106 AF XY: 0.000104

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.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 186 AN XY: 727074

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1111846

Other (OTH) AF: 0.000166 AC: 10 AN: 60386

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74360

African (AFR) AF: 0.0000966 AC: 4 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000174

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000259 AC: 1

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
1	-	-	Leber congenital amaurosis (1)
-	-	-	Bradyopsia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.053	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.95		Gain of methylation at W299 (P = 0.0335)
MVP		0.87
MPC		1.0
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.92
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908449; hg19: chr17-63193278;