rs1057518914

chrX-20193547-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_004586.3(RPS6KA3):c.533C>G(p.Ala178Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Protein kinase 1 (size 259) in uniprot entity KS6A3_HUMAN there are 30 pathogenic changes around while only 1 benign (97%) in NM_004586.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RPS6KA3
• PP5: Variant X-20193547-G-C is Pathogenic according to our data. Variant chrX-20193547-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374121.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3	c.533C>G	p.Ala178Gly	missense_variant	7/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.533C>G	p.Ala178Gly	missense_variant	7/22	1	NM_004586.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ventricular septal defect;C0020534:Hypertelorism;C0025990:Micrognathia;C0026267:Mitral valve prolapse;C0239234:Low-set ears;C0749379:Thoracolumbar scoliosis;C1096086:Abnormality of the lower limb;C1835884:Triangular face;C1839797:Deep philtrum;C1842366:Low anterior hairline;C1855728:Low posterior hairline;C4025790:Specific learning disability;C4317146:Gastroesophageal reflux;C4551485:Clinodactyly Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Feb 13, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;D;.;.;.;.
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D;.;D;D;D;D
Vest4		0.65
MutPred		0.61		Loss of stability (P = 0.0945);Loss of stability (P = 0.0945);.;.;.;.;.;.;.;.;.;.;
MVP		0.81
MPC		2.7
ClinPred		1.0	D
GERP RS		3.9
Varity_R		0.98
gMVP		0.94

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: rs1057518914; hg19: chrX-20211665;