Genetic Variant RPS6KA6:p.Met737Val (chrX-84064306-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014496.5(RPS6KA6):c.2209A>G(p.Met737Val) variant causes a missense change. The variant allele was found at a frequency of 0.000135 in 1,206,914 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 62 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 6 hem., cov: 22)

Exomes 𝑓: 0.00014 ( 0 hom. 56 hem. )

Consequence

RPS6KA6
NM_014496.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18496487).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA6	NM_014496.5 link	c.2209A>G	p.Met737Val	missense_variant	Exon 22 of 22	ENST00000262752.5	NP_055311.1	Q9UK32-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA6	ENST00000262752.5 link	c.2209A>G	p.Met737Val	missense_variant	Exon 22 of 22	1	NM_014496.5	ENSP00000262752.2		Q9UK32-1
RPS6KA6	ENST00000620340.4 link	c.2209A>G	p.Met737Val	missense_variant	Exon 22 of 22	5		ENSP00000483896.1		Q9UK32-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

111605

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

33763

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000244

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000137

AC:

AN:

175681

Hom.:

AF XY:

0.0000659

AC XY:

AN XY:

60721

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:

0.000129

Gnomad NFE exome

AF:

0.000284

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000136

AC:

149

AN:

1095309

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

360887

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:

0.00

Gnomad4 FIN exome

AF:

0.000272

Gnomad4 NFE exome

AF:

0.000162

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000125

AC:

AN:

111605

Hom.:

Cov.:

AF XY:

0.000178

AC XY:

AN XY:

33763

show subpopulations

Gnomad4 AFR

AF:

0.0000326

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000244

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000446

AC:

ExAC

AF:

0.000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2209A>G (p.M737V) alteration is located in exon 22 (coding exon 22) of the RPS6KA6 gene. This alteration results from a A to G substitution at nucleotide position 2209, causing the methionine (M) at amino acid position 737 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

0.067

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.11

.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.029

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.86

.;N

REVEL

Uncertain

0.33

Sift

Benign

0.32

.;T

Sift4G

Benign

0.48

T;T

Polyphen

0.0

.;B

Vest4

0.54

MVP

0.96

MPC

0.52

ClinPred

0.064

GERP RS

3.9

Varity_R

0.43

gMVP

0.71

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