rs56338023

Positions:

chrX-20209318-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 links:

RPS6KA3 (HGNC:):

RPS6KA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 ClinVar as [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 Lovd as [Likely_benign].

BP7

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

BS2

High Hemizygotes in GnomAd4 at 106 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 linkuse as main transcript	c.213A>G	p.Leu71Leu	synonymous_variant	3/22	ENST00000379565.9	NP_004577.1	P51812A0A384MDW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9 linkuse as main transcript	c.213A>G	p.Leu71Leu	synonymous_variant	3/22	1	NM_004586.3	ENSP00000368884.3		P51812

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

364

AN:

111751

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

106

AN XY:

33913

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

GnomAD3 exomes

AF:

0.00359

AC:

658

AN:

183190

Hom.:

AF XY:

0.00359

AC XY:

243

AN XY:

67704

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 SAS exome

AF:

0.00136

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

Gnomad4 AFR exome

AF:

0.000692

Gnomad4 AMR exome

AF:

0.000512

Gnomad4 ASJ exome

AF:

0.00156

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00140

Gnomad4 FIN exome

AF:

0.00705

Gnomad4 NFE exome

AF:

0.00477

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.00326

AC:

364

AN:

111803

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

106

AN XY:

33975

show subpopulations

Gnomad4 AFR

AF:

0.000454

Gnomad4 AMR

AF:

0.000758

Gnomad4 ASJ

AF:

0.00189

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.00113

Gnomad4 FIN

AF:

0.00766

Gnomad4 NFE

AF:

0.00531

Gnomad4 OTH

AF:

0.00260

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

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

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 12, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2019	- -

RPS6KA3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2021

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

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2016

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

DANN

Benign

0.85

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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