9-113495836-C-T

Variant names:

• chr9-113495836-C-T
• rs1830664749
• NM_001394167.1:c.404C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394167.1(RGS3):​c.404C>T​(p.Thr135Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RGS3 NM_001394167.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.09

Genes affected

RGS3 (HGNC:9999): (regulator of G protein signaling 3) This gene encodes a member of the regulator of G-protein signaling (RGS) family. This protein is a GTPase-activating protein that inhibits G-protein-mediated signal transduction. Alternative splicing and the use of alternative promoters results in multiple transcript variants encoding different isoforms. Long isoforms are largely cytosolic and plasma membrane-associated with a function in Wnt signaling and in the epithelial mesenchymal transition, while shorter N-terminally-truncated isoforms can be nuclear. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20244995).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS3	NM_001394167.1	c.404C>T	p.Thr135Ile	missense_variant	Exon 6 of 23	ENST00000695401.1	NP_001381096.1
RGS3	NM_144488.8	c.428C>T	p.Thr143Ile	missense_variant	Exon 9 of 26		NP_652759.4
RGS3	NM_001282923.2	c.410C>T	p.Thr137Ile	missense_variant	Exon 6 of 23		NP_001269852.1
RGS3	NM_017790.6	c.404C>T	p.Thr135Ile	missense_variant	Exon 6 of 18		NP_060260.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS3	ENST00000695401.1	c.404C>T	p.Thr135Ile	missense_variant	Exon 6 of 23		NM_001394167.1	ENSP00000511882.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461716 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727172

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.740C>T (p.T247I) alteration is located in exon 9 (coding exon 8) of the RGS3 gene. This alteration results from a C to T substitution at nucleotide position 740, causing the threonine (T) at amino acid position 247 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T;.
Eigen	Benign	0.092
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	.;T;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.0	M;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.52	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.36	B;B;B
Vest4		0.28
MutPred		0.39		Loss of phosphorylation at T247 (P = 0.0175);Loss of phosphorylation at T247 (P = 0.0175);.;
MVP		0.68
MPC		0.21
ClinPred		0.81	D
GERP RS		4.2
Varity_R		0.37
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1830664749; hg19: chr9-116258116; COSMIC: COSV100465169;