rs140987045

Positions:

• chrX-20209392-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_004586.3(RPS6KA3):​c.139A>G​(p.Ile47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,131,301 control chromosomes in the GnomAD database, including 1 homozygotes. There are 394 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 34 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (1 hom. 360 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.713

Genes affected

RPS6KA3 (HGNC:10432): (ribosomal protein S6 kinase A3) This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical 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. Mutations in this gene have been associated with Coffin-Lowry syndrome (CLS). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RPS6KA3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0050471127).
• BP6: Variant X-20209392-T-C is Benign according to our data. Variant chrX-20209392-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 130162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20209392-T-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3	c.139A>G	p.Ile47Val	missense_variant	3/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.139A>G	p.Ile47Val	missense_variant	3/22	1	NM_004586.3	P4

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 122 AN: 112029 Hom.: 0 Cov.: 23 AF XY: 0.000995 AC XY: 34 AN XY: 34165

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00688

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.000659

GnomAD3 exomes AF: 0.00158 AC: 290 AN: 183013 Hom.: 0 AF XY: 0.00150 AC XY: 101 AN XY: 67545

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00716

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.00124 AC: 1265 AN: 1019218 Hom.: 1 Cov.: 22 AF XY: 0.00121 AC XY: 360 AN XY: 298516

Gnomad4 AFR exome AF: 0.0000401

Gnomad4 AMR exome AF: 0.0000569

Gnomad4 ASJ exome AF: 0.0000529

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00823

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00149

GnomAD4 genome AF: 0.00109 AC: 122 AN: 112083 Hom.: 0 Cov.: 23 AF XY: 0.000993 AC XY: 34 AN XY: 34229

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00688

Gnomad4 NFE AF: 0.00139

Gnomad4 OTH AF: 0.000651

Alfa AF: 0.00105 Hom.: 43

Bravo AF: 0.000676

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00149 AC: 10

ExAC AF: 0.00175 AC: 213

EpiCase AF: 0.000763

EpiControl AF: 0.00148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 28, 2017

- -

Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.52
DEOGEN2	Benign	0.14	T;T;.;.;.;.;.;T;.;.;.;T;T
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.51	N;N;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.80	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.17	N;.;.;.;.;.;.;N;.;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	1.0	T;.;.;.;.;.;.;T;.;.;.;.;T
Sift4G	Benign	1.0	T;.;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.0	B;B;B;B;B;B;B;.;B;B;B;B;.
Vest4		0.11
MVP		0.50
MPC		1.2
ClinPred		0.0098	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.63

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

Other links and lift over

dbSNP: rs140987045; hg19: chrX-20227510;