Genetic Variant RGS11:p.Arg430His (chr16-269503-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_183337.3(RGS11):c.1289G>A(p.Arg430His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000805 in 1,612,920 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R430C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00063 ( 4 hom. )

Consequence

RGS11
NM_183337.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.53

Variant links:

Genes affected

RGS11 (HGNC:9993): (regulator of G protein signaling 11) The protein encoded by this gene belongs to the RGS (regulator of G protein signaling) family. Members of the RGS family act as GTPase-activating proteins on the alpha subunits of heterotrimeric, signal-transducing G proteins. This protein inhibits signal transduction by increasing the GTPase activity of G protein alpha subunits, thereby driving them into their inactive GDP-bound form. Alternative splicing occurs at this locus and four transcript variants encoding distinct isoforms have been identified. [provided by RefSeq, Nov 2013]

RGS11 links:

FAM234A (HGNC:14163): (family with sequence similarity 234 member A) Located in cell surface. [provided by Alliance of Genome Resources, Apr 2022]

FAM234A links:

ENSG00000286901 (HGNC:):

ENSG00000286901 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6

Variant 16-269503-C-T is Benign according to our data. Variant chr16-269503-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2645775.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RGS11	NM_183337.3 link	c.1289G>A	p.Arg430His	missense_variant, splice_region_variant	Exon 16 of 17	ENST00000397770.8	NP_899180.1	O94810-1Q4TT70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RGS11	ENST00000397770.8 link	c.1289G>A	p.Arg430His	missense_variant, splice_region_variant	Exon 16 of 17	1	NM_183337.3	ENSP00000380876.3		O94810-1

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

378

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00810

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00161

AC:

401

AN:

249822

Hom.:

AF XY:

0.00167

AC XY:

226

AN XY:

135482

show subpopulations

Gnomad AFR exome

AF:

0.00899

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00755

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000977

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000630

AC:

920

AN:

1460560

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

543

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.00753

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00611

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.000994

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152360

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00811

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00559

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00278

ESP6500AA

AF:

0.00863

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00167

AC:

203

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RGS11: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0080

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.2

M;.;.

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.5

N;N;N

REVEL

Benign

0.21

Sift

Uncertain

0.013

D;D;D

Sift4G

Uncertain

0.053

T;D;D

Polyphen

1.0

D;.;D

Vest4

0.33

MVP

0.75

MPC

0.53

ClinPred

0.035

GERP RS

4.4

Varity_R

0.16

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.75

Position offset: 0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over