rs122454130

Positions:

• chrX-20193514-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The ENST00000379565.9(RPS6KA3):​c.566T>A​(p.Ile189Lys) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPS6KA3 ENST00000379565.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Protein kinase 1 (size 259) in uniprot entity KS6A3_HUMAN there are 37 pathogenic changes around while only 1 benign (97%) in ENST00000379565.9
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-20193514-A-T is Pathogenic according to our data. Variant chrX-20193514-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 11660.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.566T>A	p.Ile189Lys	missense_variant	7/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.566T>A	p.Ile189Lys	missense_variant	7/22	1	NM_004586.3	ENSP00000368884	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Coffin-Lowry syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.6	D;.;.;.;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D;.;D;D;D;D
Vest4		0.96
MutPred		0.96		Loss of stability (P = 0.0264);Loss of stability (P = 0.0264);.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		4.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		1.0

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: rs122454130; hg19: chrX-20211632;