X-20187956-T-C

Position:

• chrX-20187956-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000379565.9(RPS6KA3):​c.646A>G​(p.Lys216Glu) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPS6KA3 ENST00000379565.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.02

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 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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, 0.949
• PP5: Variant X-20187956-T-C is Pathogenic according to our data. Variant chrX-20187956-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522803.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.646A>G	p.Lys216Glu	missense_variant	9/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.646A>G	p.Lys216Glu	missense_variant	9/22	1	NM_004586.3	ENSP00000368884	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Coffin-Lowry syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Mar 31, 2017

Likely pathogenicity based on finding this de novo in a 21-year-old female with abnormal sleep, psychiatric features (schizophrenia, bipolar disorder, major depression, hypersomnolence), loss of academic skills, small stature, fluctuating thyroid function studies (possible Hashimoto), tachycardia and mild scoliosis -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.;.;D;.;.;.;.
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.;.;.;.
Sift4G	Uncertain	0.016	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.97	D;D;B;B;B;B;B;.;B;B;B;P
Vest4		0.75
MutPred		0.85		Loss of methylation at K216 (P = 0.0075);Loss of methylation at K216 (P = 0.0075);.;.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		2.1
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.99

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: rs1555939456; hg19: chrX-20206074; COSMIC: COSV65389547;