Genetic Variant RPS6KA3:p.Thr210Ile (chrX-20188499-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP2PP3PP5_Moderate

The NM_004586.3(RPS6KA3):c.629C>T(p.Thr210Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T210T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

RPS6KA3
NM_004586.3 missense, splice_region

Scores

Splicing: ADA: 0.6358

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.60

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

Coffin-Lowry syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, G2P
intellectual disability, X-linked 19
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
symptomatic form of Coffin-Lowry syndrome in female carriers
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
non-syndromic X-linked intellectual disability
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

RPS6KA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_004586.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 4.5208 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to symptomatic form of Coffin-Lowry syndrome in female carriers, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, intellectual disability, X-linked 19.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

PP5

Variant X-20188499-G-A is Pathogenic according to our data. Variant chrX-20188499-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 559935.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004586.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	NM_004586.3	MANE Select	c.629C>T	p.Thr210Ile	missense splice_region	Exon 8 of 22	NP_004577.1
	RPS6KA3	NM_001438340.1		c.545C>T	p.Thr182Ile	missense splice_region	Exon 8 of 22	NP_001425269.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.629C>T	p.Thr210Ile	missense splice_region	Exon 8 of 22	ENSP00000368884.3
RPS6KA3	ENST00000642835.1		c.545C>T	p.Thr182Ile	missense splice_region	Exon 11 of 25	ENSP00000494769.1
RPS6KA3	ENST00000643085.1		c.545C>T	p.Thr182Ile	missense splice_region	Exon 10 of 24	ENSP00000496271.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

895333

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

260695

African (AFR)

AF:

0.00

AC:

AN:

22198

American (AMR)

AF:

0.00

AC:

AN:

32571

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17325

East Asian (EAS)

AF:

0.00

AC:

AN:

28830

South Asian (SAS)

AF:

0.00

AC:

AN:

47688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39253

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3516

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

665216

Other (OTH)

AF:

0.00

AC:

AN:

38736

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Coffin-Lowry syndrome

Pathogenic:1

Dec 04, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.031

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.095

PhyloP100

9.6

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.38

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.77

MutPred

0.79

Loss of disorder (P = 0.0742)

MVP

0.75

MPC

2.2

ClinPred

0.99

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.97

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.64

dbscSNV1_RF

Benign

0.61

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over