rs122454131
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5
The NM_004586.3(RPS6KA3):āc.803T>Cā(p.Phe268Ser) 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 Pathogenic (no stars).
Frequency
Genomes: not found (cov: 23)
Exomes š: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
RPS6KA3
NM_004586.3 missense
NM_004586.3 missense
Scores
11
4
1
Clinical Significance
Conservation
PhyloP100: 9.32
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 Pathogenic. Variant got 10 ACMG points.
PM1
?
In a domain Protein kinase 1 (size 259) in uniprot entity KS6A3_HUMAN there are 31 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, 0.988
PP5
?
Variant X-20186338-A-G is Pathogenic according to our data. Variant chrX-20186338-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 11666.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.803T>C | p.Phe268Ser | missense_variant | 10/22 | ENST00000379565.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS6KA3 | ENST00000379565.9 | c.803T>C | p.Phe268Ser | missense_variant | 10/22 | 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: 1071862Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0AN XY: 341782
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1071862
Hom.:
Cov.:
25
AF XY:
AC XY:
0
AN XY:
341782
Gnomad4 AFR exome
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Gnomad4 AMR 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: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Coffin-Lowry syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2003 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
H;H;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;D;D;D;D;D;.;D;D;D;D
Vest4
MutPred
Gain of disorder (P = 0.0089);Gain of disorder (P = 0.0089);.;.;.;.;.;.;.;.;.;.;
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