X-20172862-T-C

Position:

• chrX-20172862-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_004586.3(RPS6KA3):​c.1237A>G​(p.Arg413Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000415 in 1,204,755 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.80

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 -5 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.193367).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.1237A>G	p.Arg413Gly	missense_variant	15/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.1237A>G	p.Arg413Gly	missense_variant	15/22	1	NM_004586.3	ENSP00000368884	P4

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112589 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34739

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1092166 Hom.: 0 Cov.: 27 AF XY: 0.00000559 AC XY: 2 AN XY: 358072

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: 0.00000478

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112589 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34739

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2021	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2018	- -

Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T;T;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.075	N;N;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	2.0	N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.096
Sift	Benign	0.46	T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.49	T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0	B;B;B;B;B;B;B;.;B;B;B;B
Vest4		0.27
MutPred		0.44		Gain of catalytic residue at F418 (P = 0.1114);Gain of catalytic residue at F418 (P = 0.1114);.;.;.;.;.;.;.;.;.;.;
MVP		0.54
MPC		1.8
ClinPred		0.67	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs765914103; hg19: chrX-20190980;