rs56218010

Positions:

chrX-20234771-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

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. 12/19 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.92

Variant links:

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]

RPS6KA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPS6KA3. . Gene score misZ 4.5208 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked 19, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, symptomatic form of Coffin-Lowry syndrome in female carriers.

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. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3 linkuse as main transcript	c.113T>G	p.Ile38Ser	missense_variant	2/22	ENST00000379565.9	NP_004577.1	P51812A0A384MDW3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9 linkuse as main transcript	c.113T>G	p.Ile38Ser	missense_variant	2/22	1	NM_004586.3	ENSP00000368884.3		P51812

Frequencies

GnomAD3 genomes

AF:

0.0161

AC:

1782

AN:

110777

Hom.:

Cov.:

AF XY:

0.0147

AC XY:

485

AN XY:

32993

show subpopulations

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.:

AF XY:

0.0164

AC XY:

1113

AN XY:

67727

show subpopulations

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.:

AF XY:

0.0211

AC XY:

7348

AN XY:

349055

show subpopulations

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.:

Cov.:

AF XY:

0.0146

AC XY:

484

AN XY:

33055

show subpopulations

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:

ESP6500AA

AF:

0.00574

AC:

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.14

T;T;.;.;.;.;.;.;.;.;T;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.79

.;T;.;.;.;.;.;.;.;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.67

N;N;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.80

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

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

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