Genetic Variant RPS6KA1:p.Pro34Leu (chr1-26536962-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002953.4(RPS6KA1):c.101C>T(p.Pro34Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000057 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P34P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

RPS6KA1
NM_002953.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.171

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021833092).

BP6

Variant 1-26536962-C-T is Benign according to our data. Variant chr1-26536962-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3156195.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 40 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.101C>T	p.Pro34Leu	missense	Exon 2 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.101C>T	p.Pro34Leu	missense	Exon 2 of 22	ENSP00000363283.2	Q15418-1
RPS6KA1	ENST00000526792.5	TSL:5	c.-176C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 22	ENSP00000431651.1	Q15418-3
RPS6KA1	ENST00000529454.5	TSL:5	c.-59C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 7	ENSP00000433039.1	E9PMM7

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD2 exomes

AF:

0.0000835

AC:

AN:

251478

AF XY:

0.0000736

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111962

Other (OTH)

AF:

0.0000331

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.429

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

AF:

0.000263

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000893

AC:

AN:

41448

American (AMR)

AF:

0.000196

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000138

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.50

CADD

Benign

9.5

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.12

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.10

M_CAP

Benign

0.048

MetaRNN

Benign

0.022

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.14

PhyloP100

0.17

PROVEAN

Benign

-1.2

REVEL

Benign

0.093

Sift

Benign

0.094

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.19

MVP

0.41

ClinPred

0.0040

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

Mutation Taster

=94/6

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over