rs1325953089
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP2PP3PP5_Moderate
The NM_004586.3(RPS6KA3):c.629C>T(p.Thr210Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
RPS6KA3
NM_004586.3 missense, splice_region
NM_004586.3 missense, splice_region
Scores
5
4
7
Splicing: ADA: 0.6358
2
Clinical Significance
Conservation
PhyloP100: 9.60
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 6 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004586.3
PP2
?
Missense variant where missense usually causes diseases, RPS6KA3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.832
PP5
?
Variant X-20188499-G-A is Pathogenic according to our data. Variant chrX-20188499-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559935.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPS6KA3 | NM_004586.3 | c.629C>T | p.Thr210Ile | missense_variant, splice_region_variant | 8/22 | ENST00000379565.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS6KA3 | ENST00000379565.9 | c.629C>T | p.Thr210Ile | missense_variant, splice_region_variant | 8/22 | 1 | NM_004586.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 895333Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0AN XY: 260695
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
895333
Hom.:
Cov.:
16
AF XY:
AC XY:
0
AN XY:
260695
Gnomad4 AFR exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Coffin-Lowry syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Dec 04, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
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
Pathogenic
D;.;.;.;.;.;.;D;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.;.;.;D;.;.;.;.
Sift4G
Uncertain
D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;B;B;B;B;B;.;B;B;B;P
Vest4
MutPred
Loss of disorder (P = 0.0742);Loss of disorder (P = 0.0742);.;.;.;.;.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at