rs1555939335

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_004586.3(RPS6KA3):​c.764G>A​(p.Gly255Asp) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Consequence

RPS6KA3
NM_004586.3 missense

Scores

13
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
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.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the RPS6KA3 gene, where missense mutations are typically associated with disease (based on misZ statistic). 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). GenCC associations: The gene is linked to intellectual disability, X-linked 19, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, symptomatic form of Coffin-Lowry syndrome in female carriers.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RPS6KA3NM_004586.3 linkc.764G>A p.Gly255Asp missense_variant Exon 9 of 22 ENST00000379565.9 NP_004577.1 P51812A0A384MDW3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RPS6KA3ENST00000379565.9 linkc.764G>A p.Gly255Asp missense_variant Exon 9 of 22 1 NM_004586.3 ENSP00000368884.3 P51812

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Coffin-Lowry syndrome Uncertain:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;D;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.99
.;D;.;.;.;.;.;D;.;.;D;D
M_CAP
Pathogenic
0.48
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Pathogenic
5.0
H;H;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.95
D
PROVEAN
Pathogenic
-6.2
D;.;.;.;.;.;.;D;.;.;.;.
REVEL
Pathogenic
0.89
Sift
Pathogenic
0.0
D;.;.;.;.;.;.;D;.;.;.;.
Sift4G
Pathogenic
0.0010
D;.;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;D;D;D;D;D;D;.;D;D;D;D
Vest4
0.95
MutPred
0.96
Loss of MoRF binding (P = 0.0761);Loss of MoRF binding (P = 0.0761);.;.;.;.;.;.;.;.;.;.;
MVP
0.98
MPC
3.1
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
1.0
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555939335; hg19: chrX-20205956; API