rs1057518914
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP5_Moderate
The NM_004586.3(RPS6KA3):c.533C>G(p.Ala178Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Genomes: not found (cov: 23)
Consequence
RPS6KA3
NM_004586.3 missense
NM_004586.3 missense
Scores
4
7
5
Clinical Significance
Conservation
PhyloP100: 9.99
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 7 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
PP5
?
Variant X-20193547-G-C is Pathogenic according to our data. Variant chrX-20193547-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374121.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.533C>G | p.Ala178Gly | missense_variant | 7/22 | ENST00000379565.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS6KA3 | ENST00000379565.9 | c.533C>G | p.Ala178Gly | missense_variant | 7/22 | 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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Ventricular septal defect;C0020534:Hypertelorism;C0025990:Micrognathia;C0026267:Mitral valve prolapse;C0239234:Low-set ears;C0749379:Thoracolumbar scoliosis;C1096086:Abnormality of the lower limb;C1835884:Triangular face;C1839797:Deep philtrum;C1842366:Low anterior hairline;C1855728:Low posterior hairline;C4025790:Specific learning disability;C4317146:Gastroesophageal reflux;C4551485:Clinodactyly Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 13, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;.;.;.;.;.;.;D;.;.;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.;.;.;.;.;D;.;.;.;.
Sift4G
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
D;D;D;D;D;D;D;.;D;D;D;D
Vest4
MutPred
Loss of stability (P = 0.0945);Loss of stability (P = 0.0945);.;.;.;.;.;.;.;.;.;.;
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