Genetic Variant RGS3:p.Thr78Lys (chr9-113484181-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001394167.1(RGS3):c.233C>A(p.Thr78Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. T78M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RGS3
NM_001394167.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.84

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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.977

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.233C>A	p.Thr78Lys	missense	Exon 4 of 23	NP_001381096.1	A0A8Q3WKG2
RGS3	NM_144488.8		c.257C>A	p.Thr86Lys	missense	Exon 7 of 26	NP_652759.4	P49796-6
RGS3	NM_001282923.2		c.239C>A	p.Thr80Lys	missense	Exon 4 of 23	NP_001269852.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RGS3	ENST00000695401.1	MANE Select	c.233C>A	p.Thr78Lys	missense	Exon 4 of 23	ENSP00000511882.1	A0A8Q3WKG2
RGS3	ENST00000350696.9	TSL:5	c.569C>A	p.Thr190Lys	missense	Exon 6 of 25	ENSP00000259406.7	P49796-3
RGS3	ENST00000374140.6	TSL:2	c.569C>A	p.Thr190Lys	missense	Exon 7 of 26	ENSP00000363255.2	P49796-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461002

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726868

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:

33462

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111276

Other (OTH)

AF:

0.00

AC:

AN:

60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

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

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.0

PhyloP100

3.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.6

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.84

MutPred

0.83

Gain of ubiquitination at T190 (P = 0.0177)

MVP

0.97

MPC

0.85

ClinPred

1.0

GERP RS

5.0

Varity_R

0.79

gMVP

0.71

Mutation Taster

=58/42

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