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GeneBe

11-64368484-A-G

Variant summary

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

The NM_003942.3(RPS6KA4):c.1217A>G(p.Gln406Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,554,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 8/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

RPS6KA4
NM_003942.3 missense

Scores

1
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.25
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 (BayesDel_addAF=-0.383914).
BS2
High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPS6KA4NM_003942.3 linkuse as main transcriptc.1217A>G p.Gln406Arg missense_variant 11/17 ENST00000334205.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPS6KA4ENST00000334205.9 linkuse as main transcriptc.1217A>G p.Gln406Arg missense_variant 11/171 NM_003942.3 P1O75676-1
RPS6KA4ENST00000528057.5 linkuse as main transcriptc.1201-5A>G splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1
RPS6KA4ENST00000530504.1 linkuse as main transcriptc.1153-2A>G splice_acceptor_variant 5
RPS6KA4ENST00000528355.5 linkuse as main transcriptc.*1024A>G 3_prime_UTR_variant, NMD_transcript_variant 11/172

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152076
Hom.:
0
Cov.:
33
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:
0.00174
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
GnomAD3 exomes
AF:
0.000106
AC:
17
AN:
160220
Hom.:
0
AF XY:
0.0000702
AC XY:
6
AN XY:
85444
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00143
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000135
AC:
19
AN:
1402470
Hom.:
0
Cov.:
39
AF XY:
0.0000130
AC XY:
9
AN XY:
692332
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000491
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000172
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00174
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000445
AC:
5

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 22, 2022The c.1217A>G (p.Q406R) alteration is located in exon 11 (coding exon 11) of the RPS6KA4 gene. This alteration results from a A to G substitution at nucleotide position 1217, causing the glutamine (Q) at amino acid position 406 to be replaced by an arginine (R). 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
0.081
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.36
Cadd
Pathogenic
26
Dann
Benign
0.97
Eigen
Benign
-0.12
Eigen_PC
Benign
-0.036
FATHMM_MKL
Uncertain
0.95
D
M_CAP
Benign
0.057
D
MutationTaster
Benign
0.75
D;D;D
ClinPred
0.084
T
GERP RS
4.9

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: rs568222796; hg19: chr11-64135956; API