X-20209392-T-C

Position:

chrX-20209392-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPS6KA3. . Gene score misZ 4.5208 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked 19, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, symptomatic form of Coffin-Lowry syndrome in female carriers.

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 [Likely_benign]. Clinvar id is 130162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209392-T-C is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 linkuse as main transcript	c.139A>G	p.Ile47Val	missense_variant	3/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9 linkuse as main transcript	c.139A>G	p.Ile47Val	missense_variant	3/22	1	NM_004586.3	ENSP00000368884	P4

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

122

AN:

112029

Hom.:

Cov.:

AF XY:

0.000995

AC XY:

AN XY:

34165

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

GnomAD3 exomes

AF:

0.00158

AC:

290

AN:

183013

Hom.:

AF XY:

0.00150

AC XY:

101

AN XY:

67545

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000401

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.0000529

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00823

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00109

AC:

122

AN:

112083

Hom.:

Cov.:

AF XY:

0.000993

AC XY:

AN XY:

34229

show subpopulations

Gnomad4 AFR

AF:

0.000130

Gnomad4 AMR

AF:

0.0000946

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00688

Gnomad4 NFE

AF:

0.00139

Gnomad4 OTH

AF:

0.000651

Alfa

AF:

0.00105

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

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2021	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 13, 2023

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 28, 2017

- -

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

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;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.80

D;D;D;D

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

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