Genetic Variant NM_001394167.1:c.497C>A (chr9-113497396-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394167.1(RGS3):c.497C>A(p.Pro166Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P166L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RGS3
NM_001394167.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.939

Publications

0 publications found

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]

RGS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07031852).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394167.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGS3	NM_001394167.1	MANE Select	c.497C>A	p.Pro166Gln	missense	Exon 7 of 23	NP_001381096.1	A0A8Q3WKG2
RGS3	NM_144488.8		c.521C>A	p.Pro174Gln	missense	Exon 10 of 26	NP_652759.4	P49796-6
RGS3	NM_001282923.2		c.503C>A	p.Pro168Gln	missense	Exon 7 of 23	NP_001269852.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGS3	ENST00000695401.1	MANE Select	c.497C>A	p.Pro166Gln	missense	Exon 7 of 23	ENSP00000511882.1	A0A8Q3WKG2
RGS3	ENST00000350696.9	TSL:5	c.833C>A	p.Pro278Gln	missense	Exon 9 of 25	ENSP00000259406.7	P49796-3
RGS3	ENST00000374140.6	TSL:2	c.833C>A	p.Pro278Gln	missense	Exon 10 of 26	ENSP00000363255.2	P49796-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460906

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726828

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52746

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111786

Other (OTH)

AF:

0.00

AC:

AN:

60376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.4

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.051

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.56

M_CAP

Benign

0.015

MetaRNN

Benign

0.070

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

0.94

PrimateAI

Benign

0.30

PROVEAN

Benign

0.65

REVEL

Benign

0.013

Sift

Benign

0.099

Sift4G

Benign

0.45

Polyphen

0.0080

Vest4

0.24

MutPred

0.25

Loss of glycosylation at P278 (P = 0.0519)

MVP

0.38

MPC

0.19

ClinPred

0.23

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.30

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over