rs140987045

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.139A>G(p.Ile47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,131,301 control chromosomes in the GnomAD database, including 1 homozygotes. There are 394 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 34 hem., cov: 23)

Exomes 𝑓: 0.0012 ( 1 hom. 360 hem. )

Consequence

RPS6KA3
NM_004586.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.713

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=0.0050471127).

BP6

Variant X-20209392-T-C is Benign according to our data. Variant chrX-20209392-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 122 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 link	c.139A>G	p.Ile47Val	missense_variant	Exon 3 of 22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9 link	c.139A>G	p.Ile47Val	missense_variant	Exon 3 of 22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

122

AN:

112029

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000947

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00688

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00139

Gnomad OTH

AF:

0.000659

GnomAD2 exomes

AF:

0.00158

AC:

290

AN:

183013

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00716

Gnomad NFE exome

AF:

0.00202

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

AF:

0.00124

AC:

1265

AN:

1019218

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

360

AN XY:

298516

show subpopulations

African (AFR)

AF:

0.0000401

AC:

AN:

24948

American (AMR)

AF:

0.0000569

AC:

AN:

35125

Ashkenazi Jewish (ASJ)

AF:

0.0000529

AC:

AN:

18895

East Asian (EAS)

AF:

0.00

AC:

AN:

29866

South Asian (SAS)

AF:

0.00

AC:

AN:

52350

European-Finnish (FIN)

AF:

0.00823

AC:

332

AN:

40334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3907

European-Non Finnish (NFE)

AF:

0.00112

AC:

864

AN:

770278

Other (OTH)

AF:

0.00149

AC:

AN:

43515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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

AF:

0.00109

AC:

122

AN:

112083

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

34229

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30887

American (AMR)

AF:

0.0000946

AC:

AN:

10568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2675

European-Finnish (FIN)

AF:

0.00688

AC:

AN:

6109

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00139

AC:

AN:

53181

Other (OTH)

AF:

0.000651

AC:

AN:

1537

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000996

Hom.:

Bravo

AF:

0.000676

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000692

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00149

AC:

ExAC

AF:

0.00175

AC:

213

EpiCase

AF:

0.000763

EpiControl

AF:

0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 23, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 28, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.14

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

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.029

MetaRNN

Benign

0.0050

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

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-0.51

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

PhyloP100

0.71

PrimateAI

Uncertain

0.55

PROVEAN

Benign

0.17

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

REVEL

Benign

0.13

Sift

Benign

1.0

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

Sift4G

Benign

1.0

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

Polyphen

0.0

B;B;B;B;B;B;B;.;B;B;B;B;.

Vest4

0.11

MVP

0.50

MPC

1.2

ClinPred

0.0098

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.17

gMVP

0.63

Mutation Taster

=99/1

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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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