chrX-20188499-G-A
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP2PP3PP5_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. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T210T) has been classified as Likely benign.
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
5
6
Splicing: ADA: 0.6358
2
Clinical Significance
Conservation
PhyloP100: 9.60
Publications
2 publications found
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]
RPS6KA3 Gene-Disease associations (from GenCC):
- Coffin-Lowry syndromeInheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Genomics England PanelApp
- intellectual disability, X-linked 19Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- symptomatic form of Coffin-Lowry syndrome in female carriersInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- non-syndromic X-linked intellectual disabilityInheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 8 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004586.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 4.5208 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to symptomatic form of Coffin-Lowry syndrome in female carriers, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, intellectual disability, X-linked 19.
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 VariationId is 559935.Status of the report is criteria_provided_single_submitter, 1 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_004586.3. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RPS6KA3 | TSL:1 MANE Select | c.629C>T | p.Thr210Ile | missense splice_region | Exon 8 of 22 | ENSP00000368884.3 | P51812 | ||
| RPS6KA3 | c.677C>T | p.Thr226Ile | missense splice_region | Exon 9 of 23 | ENSP00000622758.1 | ||||
| RPS6KA3 | c.629C>T | p.Thr210Ile | missense splice_region | Exon 8 of 22 | ENSP00000586352.1 |
Frequencies
GnomAD3 genomes
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
African (AFR)
AF:
AC:
0
AN:
22198
American (AMR)
AF:
AC:
0
AN:
32571
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
17325
East Asian (EAS)
AF:
AC:
0
AN:
28830
South Asian (SAS)
AF:
AC:
0
AN:
47688
European-Finnish (FIN)
AF:
AC:
0
AN:
39253
Middle Eastern (MID)
AF:
AC:
0
AN:
3516
European-Non Finnish (NFE)
AF:
AC:
0
AN:
665216
Other (OTH)
AF:
AC:
0
AN:
38736
GnomAD4 genome
GnomAD4 genome
Cov.:
23
ClinVar
ClinVar submissions
View on ClinVar Significance:Likely pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Coffin-Lowry syndrome (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Benign
T
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
PhyloP100
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
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
Publications
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