Variant 17-59945506-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000225577.9(RPS6KB1):c.1328G>A(p.Arg443Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,439,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

RPS6KB1
ENST00000225577.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.50

Variant links:

Genes affected

RPS6KB1 (HGNC:10436): (ribosomal protein S6 kinase B1) This gene encodes a member of the ribosomal S6 kinase family of serine/threonine kinases. The encoded protein responds to mTOR (mammalian target of rapamycin) signaling to promote protein synthesis, cell growth, and cell proliferation. Activity of this gene has been associated with human cancer. Alternatively spliced transcript variants have been observed. The use of alternative translation start sites results in isoforms with longer or shorter N-termini which may differ in their subcellular localizations. There are two pseudogenes for this gene on chromosome 17. [provided by RefSeq, Jan 2013]

RPS6KB1 links:

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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;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPS6KB1. . Gene score misZ 3.9009 (greater than the threshold 3.09). Trascript score misZ 3.431 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy.

BP4

Computational evidence support a benign effect (MetaRNN=0.3438632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KB1	NM_003161.4 linkuse as main transcript	c.1328G>A	p.Arg443Gln	missense_variant	14/15	ENST00000225577.9	NP_003152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KB1	ENST00000225577.9 linkuse as main transcript	c.1328G>A	p.Arg443Gln	missense_variant	14/15	1	NM_003161.4	ENSP00000225577	A1	P23443-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250182

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135240

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1439390

Hom.:

Cov.:

AF XY:

0.00000558

AC XY:

AN XY:

717410

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000275

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

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

Apr 25, 2022

The c.1328G>A (p.R443Q) alteration is located in exon 14 (coding exon 14) of the RPS6KB1 gene. This alteration results from a G to A substitution at nucleotide position 1328, causing the arginine (R) at amino acid position 443 to be replaced by a glutamine (Q). 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

0.28

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

.;.;.;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.34

T;T;T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.8

.;.;L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.2

N;N;N;N;.

REVEL

Benign

0.28

Sift

Uncertain

0.023

D;D;D;D;.

Sift4G

Benign

0.12

T;T;T;T;D

Polyphen

0.14

.;.;.;B;.

Vest4

0.61

MutPred

0.23

.;.;Loss of MoRF binding (P = 0.0193);Loss of MoRF binding (P = 0.0193);.;

MVP

0.93

MPC

1.2

ClinPred

0.67

GERP RS

5.3

Varity_R

0.28

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over