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GeneBe

11-64361727-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_003942.3(RPS6KA4):c.737C>T(p.Thr246Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000821 in 1,607,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

RPS6KA4
NM_003942.3 missense

Scores

2
8
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.045820266).
BS2
High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS6KA4NM_003942.3 linkuse as main transcriptc.737C>T p.Thr246Met missense_variant 7/17 ENST00000334205.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS6KA4ENST00000334205.9 linkuse as main transcriptc.737C>T p.Thr246Met missense_variant 7/171 NM_003942.3 P1O75676-1

Frequencies

GnomAD3 genomes
AF:
0.0000461
AC:
7
AN:
151690
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00125
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.000164
AC:
40
AN:
244212
Hom.:
0
AF XY:
0.000225
AC XY:
30
AN XY:
133088
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00125
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000904
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.0000859
AC:
125
AN:
1455466
Hom.:
0
Cov.:
32
AF XY:
0.000115
AC XY:
83
AN XY:
724144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00133
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000832
GnomAD4 genome
AF:
0.0000461
AC:
7
AN:
151808
Hom.:
0
Cov.:
32
AF XY:
0.0000809
AC XY:
6
AN XY:
74186
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00125
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.0000422
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.000181
AC:
22

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 GeneticsApr 19, 2023The c.737C>T (p.T246M) alteration is located in exon 7 (coding exon 7) of the RPS6KA4 gene. This alteration results from a C to T substitution at nucleotide position 737, causing the threonine (T) at amino acid position 246 to be replaced by a methionine (M). 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
Uncertain
0.46
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.37
Cadd
Pathogenic
31
Dann
Uncertain
1.0
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.051
D
MetaRNN
Benign
0.046
T;T;T
MetaSVM
Benign
-0.93
T
MutationTaster
Benign
0.96
D;D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Uncertain
-3.1
D;D;D
REVEL
Benign
0.17
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
0.95
P;D;.
Vest4
0.50
MutPred
0.53
Loss of phosphorylation at T246 (P = 0.0266);Loss of phosphorylation at T246 (P = 0.0266);.;
MVP
0.36
MPC
1.2
ClinPred
0.18
T
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.46
gMVP
0.39

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: rs545430280; hg19: chr11-64129199; COSMIC: COSV53705067; COSMIC: COSV53705067; API