9-113495836-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.09
Variant links:
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]

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ACMG classification

Classification made for transcript

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
RGS3NM_001394167.1 linkc.404C>T p.Thr135Ile missense_variant Exon 6 of 23 ENST00000695401.1 NP_001381096.1
RGS3NM_144488.8 linkc.428C>T p.Thr143Ile missense_variant Exon 9 of 26 NP_652759.4 P49796-6
RGS3NM_001282923.2 linkc.410C>T p.Thr137Ile missense_variant Exon 6 of 23 NP_001269852.1 P49796B3KWG8
RGS3NM_017790.6 linkc.404C>T p.Thr135Ile missense_variant Exon 6 of 18 NP_060260.3 P49796-5B3KWG8Q53GP3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RGS3ENST00000695401.1 linkc.404C>T p.Thr135Ile missense_variant Exon 6 of 23 NM_001394167.1 ENSP00000511882.1 A0A8Q3WKG2

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
show subpopulations
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
LINK: link

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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