Variant X-20155435-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_004586.3(RPS6KA3):c.2186G>A(p.Arg729Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R729W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 22)

Consequence

RPS6KA3
NM_004586.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.57

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 Pathogenic. Variant got 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-20155436-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant X-20155435-C-T is Pathogenic according to our data. Variant chrX-20155435-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3 linkuse as main transcript	c.2186G>A	p.Arg729Gln	missense_variant	22/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9 linkuse as main transcript	c.2186G>A	p.Arg729Gln	missense_variant	22/22	1	NM_004586.3	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16879200, 10094187, 11180593) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Coffin-Lowry syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2018

- -

Intellectual disability

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D;.;.;.;.;.;.;.;.;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

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

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Uncertain

2.9

M;M;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.4

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

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.60

MutPred

0.84

Loss of MoRF binding (P = 0.065);Loss of MoRF binding (P = 0.065);.;.;.;.;.;.;.;.;.;.;

MVP

0.95

MPC

2.9

ClinPred

1.0

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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