rs56338023

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_004586.3(RPS6KA3):c.213A>G(p.Leu71Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,190,051 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,513 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., 106 hem., cov: 23)

Exomes 𝑓: 0.0042 ( 7 hom. 1407 hem. )

Consequence

RPS6KA3
NM_004586.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0450

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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant X-20209318-T-C is Benign according to our data. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209318-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.045 with no splicing effect.

BS2

High AC in GnomAd4 at 364 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 link	c.213A>G	p.Leu71Leu	synonymous_variant	Exon 3 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.213A>G	p.Leu71Leu	synonymous_variant	Exon 3 of 22	1	NM_004586.3	ENSP00000368884.3		P51812

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

364

AN:

111751

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000455

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000759

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00112

Gnomad FIN

AF:

0.00766

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.00531

Gnomad OTH

AF:

0.00263

GnomAD2 exomes

AF:

0.00359

AC:

658

AN:

183190

AF XY:

0.00359

show subpopulations

Gnomad AFR exome

AF:

0.000760

Gnomad AMR exome

AF:

0.000474

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00785

Gnomad NFE exome

AF:

0.00572

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00417

AC:

4496

AN:

1078248

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

1407

AN XY:

346422

show subpopulations

African (AFR)

AF:

0.000692

AC:

AN:

26008

American (AMR)

AF:

0.000512

AC:

AN:

35178

Ashkenazi Jewish (ASJ)

AF:

0.00156

AC:

AN:

19254

East Asian (EAS)

AF:

0.00

AC:

AN:

30088

South Asian (SAS)

AF:

0.00140

AC:

AN:

53688

European-Finnish (FIN)

AF:

0.00705

AC:

285

AN:

40447

Middle Eastern (MID)

AF:

0.000763

AC:

AN:

3932

European-Non Finnish (NFE)

AF:

0.00477

AC:

3928

AN:

824188

Other (OTH)

AF:

0.00306

AC:

139

AN:

45465

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

135

269

404

538

673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.00326

AC:

364

AN:

111803

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

106

AN XY:

33975

show subpopulations

African (AFR)

AF:

0.000454

AC:

AN:

30846

American (AMR)

AF:

0.000758

AC:

AN:

10554

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

2641

East Asian (EAS)

AF:

0.000280

AC:

AN:

3576

South Asian (SAS)

AF:

0.00113

AC:

AN:

2663

European-Finnish (FIN)

AF:

0.00766

AC:

AN:

6009

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00531

AC:

282

AN:

53072

Other (OTH)

AF:

0.00260

AC:

AN:

1539

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00453

Hom.:

Bravo

AF:

0.00246

EpiCase

AF:

0.00447

EpiControl

AF:

0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 12, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 19, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 03, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RPS6KA3-related disorder

Benign:1

Oct 19, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Inborn genetic diseases

Benign:1

Aug 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

BayesDel_noAF

Benign

-0.54

CADD

Benign

9.4

(source)

DANN

Benign

0.85

PhyloP100

-0.045

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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