rs56218010

chrX-20234771-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004586.3(RPS6KA3):c.113T>G(p.Ile38Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0217 in 1,191,596 control chromosomes in the GnomAD database, including 218 homozygotes. There are 7,832 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (13 hom., 484 hem., cov: 23)
  • Exomes 𝑓: 0.022 (205 hom. 7348 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.92

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RPS6KA3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0039746463).
• BP6: Variant X-20234771-A-C is Benign according to our data. Variant chrX-20234771-A-C is described in ClinVar as [Benign]. Clinvar id is 95147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-20234771-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0161 (1781/110829) while in subpopulation NFE AF= 0.0267 (1410/52904). AF 95% confidence interval is 0.0255. There are 13 homozygotes in gnomad4. There are 484 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3	c.113T>G	p.Ile38Ser	missense_variant	2/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.113T>G	p.Ile38Ser	missense_variant	2/22	1	NM_004586.3	P4

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 1782 AN: 110777 Hom.: 13 Cov.: 23 AF XY: 0.0147 AC XY: 485 AN XY: 32993

Gnomad AFR AF: 0.00394

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00904

Gnomad ASJ AF: 0.00265

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0135

GnomAD3 exomes AF: 0.0161 AC: 2948 AN: 183231 Hom.: 22 AF XY: 0.0164 AC XY: 1113 AN XY: 67727

Gnomad AFR exome AF: 0.00441

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00294

Gnomad EAS exome AF: 0.0000722

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0223 AC: 24111 AN: 1080767 Hom.: 205 Cov.: 27 AF XY: 0.0211 AC XY: 7348 AN XY: 349055

Gnomad4 AFR exome AF: 0.00280

Gnomad4 AMR exome AF: 0.00543

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.0105

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0262

Gnomad4 OTH exome AF: 0.0181

GnomAD4 genome AF: 0.0161 AC: 1781 AN: 110829 Hom.: 13 Cov.: 23 AF XY: 0.0146 AC XY: 484 AN XY: 33055

Gnomad4 AFR AF: 0.00393

Gnomad4 AMR AF: 0.00903

Gnomad4 ASJ AF: 0.00265

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.0117

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.0267

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0252 Hom.: 1107

Bravo AF: 0.0147

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0173 AC: 50

ESP6500AA AF: 0.00574 AC: 22

ESP6500EA AF: 0.0279 AC: 188

ExAC AF: 0.0171 AC: 2080

EpiCase AF: 0.0250

EpiControl AF: 0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 12, 2012	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 26, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Benign	0.86
DEOGEN2	Benign	0.14	T;T;.;.;.;.;.;.;.;.;T;T
FATHMM_MKL	Uncertain	0.80	D
MetaRNN	Benign	0.0040	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.67	N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.82	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	1.9	N;.;.;.;.;.;.;.;.;.;.;N
REVEL	Benign	0.19
Sift	Benign	0.81	T;.;.;.;.;.;.;.;.;.;.;T
Sift4G	Benign	0.74	T;.;.;.;.;.;.;.;.;.;.;T
Polyphen		0.0	B;B;B;B;B;B;B;B;B;B;B;.
Vest4		0.15
MPC		2.0
ClinPred		0.013	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.77

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: rs56218010; hg19: chrX-20252889;