rs387906703
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_004586.3(RPS6KA3):c.343A>T(p.Thr115Ser) variant causes a missense change. 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T115T) has been classified as Uncertain significance.
Frequency
Genomes: not found (cov: 23)
Consequence
RPS6KA3
NM_004586.3 missense
NM_004586.3 missense
Scores
5
2
9
Clinical Significance
Conservation
PhyloP100: 5.92
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a domain Protein kinase 1 (size 259) in uniprot entity KS6A3_HUMAN there are 30 pathogenic changes around while only 1 benign (97%) in NM_004586.3
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RPS6KA3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.908
PP5
?
Variant X-20195128-T-A is Pathogenic according to our data. Variant chrX-20195128-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 29932.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPS6KA3 | NM_004586.3 | c.343A>T | p.Thr115Ser | missense_variant | 5/22 | ENST00000379565.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS6KA3 | ENST00000379565.9 | c.343A>T | p.Thr115Ser | missense_variant | 5/22 | 1 | NM_004586.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Cov.: 25
GnomAD4 exome
Cov.:
25
GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 19 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2006 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;.;.;.;.;.;.;N;.;.;.;.
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;.;T;.;.;.;.
Sift4G
Benign
T;.;.;.;.;.;.;.;.;.;.;.
Polyphen
B;B;P;P;P;P;P;.;P;P;P;B
Vest4
MutPred
Gain of disorder (P = 0.0443);Gain of disorder (P = 0.0443);.;.;.;.;.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at