chrX-20156115-T-TA
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_004586.3(RPS6KA3):c.2093_2094insT(p.Val699SerfsTer15) variant causes a frameshift 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 22)
Consequence
RPS6KA3
NM_004586.3 frameshift
NM_004586.3 frameshift
Scores
Not classified
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-20156115-T-TA is Pathogenic according to our data. Variant chrX-20156115-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 2951625.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.2093_2094insT | p.Val699SerfsTer15 | frameshift_variant | 21/22 | ENST00000379565.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS6KA3 | ENST00000379565.9 | c.2093_2094insT | p.Val699SerfsTer15 | frameshift_variant | 21/22 | 1 | NM_004586.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change creates a premature translational stop signal (p.Val699Serfs*15) in the RPS6KA3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 42 amino acid(s) of the RPS6KA3 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RPS6KA3-related conditions. This variant disrupts a region of the RPS6KA3 protein in which other variant(s) (p.Arg729Trp) have been determined to be pathogenic (PMID: 16879200, 30740391). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.