Genetic Variant RPS6KA1:p.Pro11Ser (chr1-26529951-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002953.4(RPS6KA1):c.31C>T(p.Pro11Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000078 in 1,282,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P11T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

RPS6KA1
NM_002953.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.429

Publications

1 publications found

Variant links:

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]

RPS6KA1 links:

LOC124903884 (HGNC:):

LOC124903884 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22104535).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002953.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA1	NM_002953.4	MANE Select	c.31C>T	p.Pro11Ser	missense	Exon 1 of 22	NP_002944.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KA1	ENST00000374168.7	TSL:1 MANE Select	c.31C>T	p.Pro11Ser	missense	Exon 1 of 22	ENSP00000363283.2	Q15418-1
RPS6KA1	ENST00000952528.1		c.31C>T	p.Pro11Ser	missense	Exon 1 of 22	ENSP00000622587.1
RPS6KA1	ENST00000952527.1		c.31C>T	p.Pro11Ser	missense	Exon 1 of 22	ENSP00000622586.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000138

AC:

AN:

72384

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000375

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000780

AC:

AN:

1282160

Hom.:

Cov.:

AF XY:

0.00000632

AC XY:

AN XY:

632664

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25672

American (AMR)

AF:

0.00

AC:

AN:

23598

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21830

East Asian (EAS)

AF:

0.00

AC:

AN:

25920

South Asian (SAS)

AF:

0.00

AC:

AN:

70874

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3674

European-Non Finnish (NFE)

AF:

0.00000974

AC:

AN:

1026884

Other (OTH)

AF:

0.00

AC:

AN:

51964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.067

Eigen

Benign

0.021

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.15

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.0

PhyloP100

0.43

PROVEAN

Benign

0.27

REVEL

Benign

0.20

Sift

Benign

0.75

Sift4G

Benign

0.73

Polyphen

0.91

Vest4

0.19

MutPred

0.20

Gain of phosphorylation at P11 (P = 0.0461)

MVP

0.75

ClinPred

0.19

GERP RS

3.0

PromoterAI

-0.0089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.080

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over