Genetic Variant RPS6KA6:p.Ile561Val (chrX-84102132-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014496.5(RPS6KA6):c.1681A>G(p.Ile561Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000278 in 1,080,654 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000028 ( 0 hom. 1 hem. )

Consequence

RPS6KA6
NM_014496.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

Variant links:

Genes affected

RPS6KA6 (HGNC:10435): (ribosomal protein S6 kinase A6) This gene encodes a member of ribosomal S6 kinase family, serine-threonine protein kinases which are regulated by growth factors. The encoded protein may be distinct from other members of this family, however, as studies suggest it is not growth factor dependent and may not participate in the same signaling pathways. [provided by RefSeq, Jan 2010]

RPS6KA6 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18385842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA6	NM_014496.5 link	c.1681A>G	p.Ile561Val	missense_variant	Exon 18 of 22	ENST00000262752.5	NP_055311.1	Q9UK32-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RPS6KA6	ENST00000262752.5 link	c.1681A>G	p.Ile561Val	missense_variant	Exon 18 of 22	1	NM_014496.5	ENSP00000262752.2	Q9UK32-1
RPS6KA6	ENST00000620340.4 link	c.1681A>G	p.Ile561Val	missense_variant	Exon 18 of 22	5		ENSP00000483896.1	Q9UK32-2
RPS6KA6	ENST00000495332.1 link	n.354-40A>G		intron_variant	Intron 3 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000582

AC:

AN:

171937

Hom.:

AF XY:

0.00

AC XY:

AN XY:

57785

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000389

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1080654

Hom.:

Cov.:

AF XY:

0.00000287

AC XY:

AN XY:

348256

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000580

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000121

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1681A>G (p.I561V) alteration is located in exon 18 (coding exon 18) of the RPS6KA6 gene. This alteration results from a A to G substitution at nucleotide position 1681, causing the isoleucine (I) at amino acid position 561 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

.;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

D;D

M_CAP

Benign

0.0093

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.41

N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.89

.;N

REVEL

Benign

0.076

Sift

Benign

0.30

.;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0070

.;B

Vest4

0.33

MutPred

0.48

Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);

MVP

0.52

MPC

0.61

ClinPred

0.28

GERP RS

5.1

Varity_R

0.36

gMVP

0.27

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.

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