1-26573248-G-A
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_002953.4(RPS6KA1):c.1972G>A(p.Val658Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000582 in 1,613,990 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000061 ( 1 hom. )
Consequence
RPS6KA1
NM_002953.4 missense
NM_002953.4 missense
Scores
5
13
Clinical Significance
Conservation
PhyloP100: 4.97
Genes affected
RPS6KA1 (HGNC:10430): (ribosomal protein S6 kinase A1) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical 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. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.13672745).
BS2
?
High AC in GnomAd at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RPS6KA1 | NM_002953.4 | c.1972G>A | p.Val658Met | missense_variant | 21/22 | ENST00000374168.7 | |
RPS6KA1 | NM_001006665.2 | c.1999G>A | p.Val667Met | missense_variant | 20/21 | ||
RPS6KA1 | NM_001330441.2 | c.1924G>A | p.Val642Met | missense_variant | 20/21 | ||
RPS6KA1 | XM_024448871.2 | c.1696G>A | p.Val566Met | missense_variant | 21/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RPS6KA1 | ENST00000374168.7 | c.1972G>A | p.Val658Met | missense_variant | 21/22 | 1 | NM_002953.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.000127 AC: 32AN: 251248Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135816
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GnomAD4 exome AF: 0.0000609 AC: 89AN: 1461816Hom.: 1 Cov.: 33 AF XY: 0.0000866 AC XY: 63AN XY: 727218
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GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
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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 submitter | clinical testing | Ambry Genetics | Jun 30, 2023 | The c.1999G>A (p.V667M) alteration is located in exon 20 (coding exon 20) of the RPS6KA1 gene. This alteration results from a G to A substitution at nucleotide position 1999, causing the valine (V) at amino acid position 667 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T;.;.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T;D;T
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
B;.;.;.;B;.
Vest4
MutPred
Gain of disorder (P = 0.0607);.;.;.;.;.;
MVP
MPC
0.98
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at