chrX-20188499-G-A

Position:

• chrX-20188499-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_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 (★).

• 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

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 6 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, 0.832
• 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 id is 559935.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.629C>T	p.Thr210Ile	missense_variant, splice_region_variant	8/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.629C>T	p.Thr210Ile	missense_variant, splice_region_variant	8/22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 895333 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 260695

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Dec 04, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.095	N;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.5	D;.;.;.;.;.;.;D;.;.;.;.
REVEL	Uncertain	0.38
Sift	Uncertain	0.0040	D;.;.;.;.;.;.;D;.;.;.;.
Sift4G	Uncertain	0.012	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		1.0	D;D;B;B;B;B;B;.;B;B;B;P
Vest4		0.77
MutPred		0.79		Loss of disorder (P = 0.0742);Loss of disorder (P = 0.0742);.;.;.;.;.;.;.;.;.;.;
MVP		0.75
MPC		2.2
ClinPred		0.99	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.97

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

LitVar

Other links and lift over

dbSNP: rs1325953089; hg19: chrX-20206617;