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GeneBe

11-64361883-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003942.3(RPS6KA4):c.787C>T(p.Pro263Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P263A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

RPS6KA4
NM_003942.3 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0440
Variant links:
Genes affected
RPS6KA4 (HGNC:10433): (ribosomal protein S6 kinase A4) 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 CREB1 and ATF1. The encoded protein can also phosphorylate histone H3 to regulate certain inflammatory genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.070789486).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS6KA4NM_003942.3 linkuse as main transcriptc.787C>T p.Pro263Ser missense_variant 8/17 ENST00000334205.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS6KA4ENST00000334205.9 linkuse as main transcriptc.787C>T p.Pro263Ser missense_variant 8/171 NM_003942.3 P1O75676-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1460714
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726700
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 14, 2021The c.787C>T (p.P263S) alteration is located in exon 8 (coding exon 8) of the RPS6KA4 gene. This alteration results from a C to T substitution at nucleotide position 787, causing the proline (P) at amino acid position 263 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
Cadd
Benign
11
Dann
Benign
0.90
Eigen
Benign
-0.70
Eigen_PC
Benign
-0.64
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.83
T;T;T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.071
T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.46
T
PROVEAN
Benign
0.93
N;N;N
REVEL
Benign
0.023
Sift
Benign
0.32
T;T;T
Sift4G
Benign
0.59
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.14
MutPred
0.25
Gain of phosphorylation at P263 (P = 0.0465);Gain of phosphorylation at P263 (P = 0.0465);.;
MVP
0.20
MPC
0.43
ClinPred
0.085
T
GERP RS
0.96
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.031
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs772788703; hg19: chr11-64129355; COSMIC: COSV105115096; COSMIC: COSV105115096; API