chrX-20209307-C-A

Position:

• chrX-20209307-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_004586.3(RPS6KA3):​c.224G>T​(p.Gly75Val) 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: 22)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• 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, 0.991
• PP5: Variant X-20209307-C-A is Pathogenic according to our data. Variant chrX-20209307-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 11651.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.224G>T	p.Gly75Val	missense_variant	3/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.224G>T	p.Gly75Val	missense_variant	3/22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 22

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

Dec 12, 1996

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;D;.;.;.;.;.;T;.;.;.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;.;.;.;.;D;.;.;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.4	H;H;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.9	D;.;.;.;.;.;.;D;.;.;.;.;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;D;.;.;.;.;D
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;.;.;D
Polyphen		1.0	D;D;D;D;D;D;D;.;D;D;D;D;.
Vest4		0.98
MutPred		0.98		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		3.1
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.97

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: rs122454124; hg19: chrX-20227425;