X-20155487-G-A

Variant names:

• chrX-20155487-G-A
• rs1323142539
• NM_004586.3:c.2134C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_004586.3(RPS6KA3):​c.2134C>T​(p.Arg712Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,097,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 2 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36

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_benign. Variant got -4 ACMG points.

• PP2: Missense variant in the RPS6KA3 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 4.5208 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, X-linked 19, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, symptomatic form of Coffin-Lowry syndrome in female carriers.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2885095).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.2134C>T	p.Arg712Cys	missense_variant	Exon 22 of 22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.2134C>T	p.Arg712Cys	missense_variant	Exon 22 of 22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1097230 Hom.: 0 Cov.: 29 AF XY: 0.00000552 AC XY: 2 AN XY: 362594

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: 0.00000476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.4	N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.16
Sift	Uncertain	0.022	D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.033	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;B;P;P;P;P;P;.;P;P;P;B
Vest4		0.51
MutPred		0.50		Loss of solvent accessibility (P = 0.0079);Loss of solvent accessibility (P = 0.0079);.;.;.;.;.;.;.;.;.;.;
MVP		0.81
MPC		1.9
ClinPred		0.93	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1323142539; hg19: chrX-20173605; COSMIC: COSV65387275;