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GeneBe

11-64369458-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003942.3(RPS6KA4):c.1441C>G(p.Leu481Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

RPS6KA4
NM_003942.3 missense

Scores

1
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS6KA4NM_003942.3 linkuse as main transcriptc.1441C>G p.Leu481Val missense_variant 13/17 ENST00000334205.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS6KA4ENST00000334205.9 linkuse as main transcriptc.1441C>G p.Leu481Val missense_variant 13/171 NM_003942.3 P1O75676-1
RPS6KA4ENST00000528057.5 linkuse as main transcriptc.1420C>G p.Leu474Val missense_variant 13/171
RPS6KA4ENST00000530504.1 linkuse as main transcriptc.1375C>G p.Leu459Val missense_variant 13/175
RPS6KA4ENST00000528355.5 linkuse as main transcriptc.*1248C>G 3_prime_UTR_variant, NMD_transcript_variant 13/172

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1453856
Hom.:
0
Cov.:
34
AF XY:
0.00000553
AC XY:
4
AN XY:
723096
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Asia WGS
AF:
0.000867
AC:
3
AN:
3476

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 GeneticsNov 15, 2021The c.1441C>G (p.L481V) alteration is located in exon 13 (coding exon 13) of the RPS6KA4 gene. This alteration results from a C to G substitution at nucleotide position 1441, causing the leucine (L) at amino acid position 481 to be replaced by a valine (V). 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
0.12
BayesDel_addAF
Benign
-0.072
T
BayesDel_noAF
Benign
-0.34
Cadd
Uncertain
23
Dann
Uncertain
0.99
Eigen
Benign
0.14
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.53
D;D;D
MetaSVM
Benign
-0.89
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Benign
0.23
Sift
Benign
0.12
T;T;T
Sift4G
Uncertain
0.042
D;D;T
Polyphen
0.95
P;P;.
Vest4
0.53
MutPred
0.77
.;Loss of sheet (P = 0.302);.;
MVP
0.54
MPC
1.6
ClinPred
0.83
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9
Varity_R
0.11
gMVP
0.93

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: rs868745357; hg19: chr11-64136930; API