chr17-65137551-G-T

Position:

• chr17-65137551-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003835.4(RGS9):​c.11G>T​(p.Arg4Leu) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RGS9 NM_003835.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28405967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RGS9	NM_003835.4	c.11G>T	p.Arg4Leu	missense_variant	1/19	ENST00000262406.10	NP_003826.2
RGS9	NM_001081955.3	c.11G>T	p.Arg4Leu	missense_variant	1/19		NP_001075424.1
RGS9	NM_001165933.2	c.11G>T	p.Arg4Leu	missense_variant	1/17		NP_001159405.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RGS9	ENST00000262406.10	c.11G>T	p.Arg4Leu	missense_variant	1/19	1	NM_003835.4	ENSP00000262406	P4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with RGS9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 4 of the RGS9 protein (p.Arg4Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.27	.;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.90	.;L;L
MutationTaster	Benign	0.57	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.023	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.42
MutPred		0.34		Loss of MoRF binding (P = 0.0122);Loss of MoRF binding (P = 0.0122);Loss of MoRF binding (P = 0.0122);
MVP		0.70
MPC		0.23
ClinPred		0.67	D
GERP RS		4.1
Varity_R		0.24
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-63133669; COSMIC: COSV52229839; COSMIC: COSV52229839;