17-65225096-G-T

Variant names:

• chr17-65225096-G-T
• rs34797451
• NM_003835.4:c.1502G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003835.4(RGS9):​c.1502G>T​(p.Arg501Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R501H) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RGS9 NM_003835.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.604
• Publications: 0 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: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS9	NM_003835.4	MANE Select	c.1502G>T	p.Arg501Leu	missense	Exon 18 of 19	NP_003826.2
	RGS9	NM_001081955.3		c.1493G>T	p.Arg498Leu	missense	Exon 18 of 19	NP_001075424.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RGS9	ENST00000262406.10	TSL:1 MANE Select	c.1502G>T	p.Arg501Leu	missense	Exon 18 of 19	ENSP00000262406.9
	RGS9	ENST00000449996.7	TSL:1	c.1493G>T	p.Arg498Leu	missense	Exon 18 of 19	ENSP00000396329.3
	RGS9	ENST00000443584.7	TSL:1	c.1493G>T	p.Arg498Leu	missense	Exon 18 of 18	ENSP00000405814.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 501 of the RGS9 protein (p.Arg501Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RGS9-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0038
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.60
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.12
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.096	T
Polyphen		0.0020	B
Vest4		0.26
MutPred		0.27		Loss of MoRF binding (P = 0.0089)
MVP		0.55
MPC		0.31
ClinPred		0.61	D
GERP RS		3.9
Varity_R		0.19
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34797451; hg19: chr17-63221214;