rs144984628

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_004586.3(RPS6KA3):c.2168G>A(p.Arg723His) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,208,024 control chromosomes in the GnomAD database, including 3 homozygotes. There are 471 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 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. R723C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., 44 hem., cov: 22)

Exomes 𝑓: 0.0013 ( 3 hom. 427 hem. )

Consequence

RPS6KA3
NM_004586.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 3.80

Publications

2 publications found

Variant links:

Genes affected

RPS6KA3 (HGNC:10432): (ribosomal protein S6 kinase A3) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS). [provided by RefSeq, Jul 2008]

RPS6KA3 Gene-Disease associations (from GenCC):

Coffin-Lowry syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, G2P
intellectual disability, X-linked 19
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
symptomatic form of Coffin-Lowry syndrome in female carriers
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

RPS6KA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 4.5208 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to symptomatic form of Coffin-Lowry syndrome in female carriers, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, intellectual disability, X-linked 19.

BP4

Computational evidence support a benign effect (MetaRNN=0.008939147).

BP6

Variant X-20155453-C-T is Benign according to our data. Variant chrX-20155453-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 212070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 140 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 link	c.2168G>A	p.Arg723His	missense_variant	Exon 22 of 22	ENST00000379565.9	NP_004577.1	P51812A0A384MDW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9 link	c.2168G>A	p.Arg723His	missense_variant	Exon 22 of 22	1	NM_004586.3	ENSP00000368884.3		P51812

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

140

AN:

111111

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000983

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00895

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00158

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00151

AC:

275

AN:

181908

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00993

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00129

AC:

1410

AN:

1096857

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

427

AN XY:

362239

show subpopulations

African (AFR)

AF:

0.000152

AC:

AN:

26369

American (AMR)

AF:

0.0000284

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19369

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54115

European-Finnish (FIN)

AF:

0.00999

AC:

405

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00113

AC:

954

AN:

840873

Other (OTH)

AF:

0.000977

AC:

AN:

46064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00126

AC:

140

AN:

111167

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

33389

show subpopulations

African (AFR)

AF:

0.0000980

AC:

AN:

30602

American (AMR)

AF:

0.00

AC:

AN:

10376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3566

South Asian (SAS)

AF:

0.00

AC:

AN:

2615

European-Finnish (FIN)

AF:

0.00895

AC:

AN:

5920

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00158

AC:

AN:

53040

Other (OTH)

AF:

0.00

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.000654

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00134

AC:

ExAC

AF:

0.00129

AC:

157

EpiCase

AF:

0.00125

EpiControl

AF:

0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 22, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RPS6KA3 c.2168G>A (p.Arg723His) results in a non-conservative amino acid change located in the Ribosomal protein S6 kinase alpha-3, C-terminal catalytic domain (IPR041905) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 203701 control chromosomes, predominantly at a frequency of 0.0099 within the Finnish subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RPS6KA3 causing Coffin-Lowry Syndrome phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Finnish origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2), likely benign (n=2) and benign (n=4). Based on the evidence outlined above, the variant was classified as benign. -

Aug 02, 2017

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RPS6KA3: PP2, BS1, BS2 -

Jun 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31019283, 30378261, 16879200, 11180593) -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Coffin-Lowry syndrome

Benign:1

Aug 22, 2023

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RPS6KA3-related disorder

Benign:1

Oct 27, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19

Benign:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 05, 2017

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability, X-linked 19

Benign:1

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;T;.;.;.;.;.;.;.;.;.;T

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

.;D;.;.;.;.;.;D;.;.;D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.0089

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.0

N;N;.;.;.;.;.;.;.;.;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.73

N;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.24

Sift

Benign

0.047

D;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.10

T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.38

B;B;P;P;P;P;P;.;P;P;P;B

Vest4

0.74

MVP

0.91

MPC

2.1

ClinPred

0.016

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.58

Mutation Taster

=90/10

polymorphism (auto)

(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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rs144984628

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over