rs765914103

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_004586.3(RPS6KA3):c.1237A>G(p.Arg413Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,204,755 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000037 ( 0 hom. 2 hem. )

Consequence

RPS6KA3
NM_004586.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.80

Publications

0 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: Likely_benign. The variant received -5 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=0.193367).

BS2

High Hemizygotes in GnomAdExome4 at 2 AD,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 link	c.1237A>G	p.Arg413Gly	missense_variant	Exon 15 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.1237A>G	p.Arg413Gly	missense_variant	Exon 15 of 22	1	NM_004586.3	ENSP00000368884.3		P51812

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112589

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

182390

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000366

AC:

AN:

1092166

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

358072

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26264

American (AMR)

AF:

0.00

AC:

AN:

35153

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19309

East Asian (EAS)

AF:

0.00

AC:

AN:

30076

South Asian (SAS)

AF:

0.00

AC:

AN:

53878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4059

European-Non Finnish (NFE)

AF:

0.00000478

AC:

AN:

837040

Other (OTH)

AF:

0.00

AC:

AN:

45895

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112589

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34739

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31037

American (AMR)

AF:

0.00

AC:

AN:

10631

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3626

South Asian (SAS)

AF:

0.00

AC:

AN:

2759

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6155

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53291

Other (OTH)

AF:

0.00

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 21, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

Nov 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.12

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

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.87

.;D;.;.;.;.;.;D;.;.;D;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.19

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.075

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

PhyloP100

1.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

2.0

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

REVEL

Benign

0.096

Sift

Benign

0.46

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

Sift4G

Benign

0.49

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

Polyphen

0.0

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

Vest4

0.27

MutPred

0.44

Gain of catalytic residue at F418 (P = 0.1114);Gain of catalytic residue at F418 (P = 0.1114);.;.;.;.;.;.;.;.;.;.;

MVP

0.54

MPC

1.8

ClinPred

0.67

GERP RS

5.1

PromoterAI

-0.0022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.82

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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