rs56218010

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004586.3(RPS6KA3):c.113T>G(p.Ile38Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0217 in 1,191,596 control chromosomes in the GnomAD database, including 218 homozygotes. There are 7,832 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 13 hom., 484 hem., cov: 23)

Exomes 𝑓: 0.022 ( 205 hom. 7348 hem. )

Consequence

RPS6KA3
NM_004586.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.92

Publications

11 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 -19 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=0.0039746463).

BP6

Variant X-20234771-A-C is Benign according to our data. Variant chrX-20234771-A-C is described in ClinVar as Benign. ClinVar VariationId is 95147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0161 (1781/110829) while in subpopulation NFE AF = 0.0267 (1410/52904). AF 95% confidence interval is 0.0255. There are 13 homozygotes in GnomAd4. There are 484 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 1781 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 link	c.113T>G	p.Ile38Ser	missense_variant	Exon 2 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.113T>G	p.Ile38Ser	missense_variant	Exon 2 of 22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

1782

AN:

110777

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00394

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00904

Gnomad ASJ

AF:

0.00265

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.0121

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0266

Gnomad OTH

AF:

0.0135

GnomAD2 exomes

AF:

0.0161

AC:

2948

AN:

183231

AF XY:

0.0164

show subpopulations

Gnomad AFR exome

AF:

0.00441

Gnomad AMR exome

AF:

0.00558

Gnomad ASJ exome

AF:

0.00294

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.0174

Gnomad NFE exome

AF:

0.0262

Gnomad OTH exome

AF:

0.0172

GnomAD4 exome

AF:

0.0223

AC:

24111

AN:

1080767

Hom.:

205

Cov.:

AF XY:

0.0211

AC XY:

7348

AN XY:

349055

show subpopulations

African (AFR)

AF:

0.00280

AC:

AN:

26098

American (AMR)

AF:

0.00543

AC:

191

AN:

35172

Ashkenazi Jewish (ASJ)

AF:

0.00275

AC:

AN:

19275

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30076

South Asian (SAS)

AF:

0.0105

AC:

564

AN:

53754

European-Finnish (FIN)

AF:

0.0185

AC:

749

AN:

40496

Middle Eastern (MID)

AF:

0.00636

AC:

AN:

4085

European-Non Finnish (NFE)

AF:

0.0262

AC:

21629

AN:

826350

Other (OTH)

AF:

0.0181

AC:

825

AN:

45461

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

707

1415

2122

2830

3537

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

792

1584

2376

3168

3960

<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:

0.0161

AC:

1781

AN:

110829

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

484

AN XY:

33055

show subpopulations

African (AFR)

AF:

0.00393

AC:

120

AN:

30509

American (AMR)

AF:

0.00903

AC:

AN:

10410

Ashkenazi Jewish (ASJ)

AF:

0.00265

AC:

AN:

2637

East Asian (EAS)

AF:

0.000282

AC:

AN:

3548

South Asian (SAS)

AF:

0.0117

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.0154

AC:

AN:

5784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0267

AC:

1410

AN:

52904

Other (OTH)

AF:

0.0133

AC:

AN:

1500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

137

206

274

343

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0236

Hom.:

1118

Bravo

AF:

0.0147

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0173

AC:

ESP6500AA

AF:

0.00574

AC:

ESP6500EA

AF:

0.0279

AC:

188

ExAC

AF:

0.0171

AC:

2080

EpiCase

AF:

0.0250

EpiControl

AF:

0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jan 10, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 12, 2012

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Oct 26, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Apr 26, 2016

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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.14

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

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.0

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

MetaRNN

Benign

0.0040

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.67

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

PhyloP100

3.9

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

1.9

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

REVEL

Benign

0.19

Sift

Benign

0.81

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

Sift4G

Benign

0.74

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

Vest4

0.15

ClinPred

0.013

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.77

Mutation Taster

=100/0

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