X-20165030-T-C

Position:

• chrX-20165030-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004586.3(RPS6KA3):​c.1633A>G​(p.Ile545Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,088,061 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.1633A>G	p.Ile545Val	missense_variant	18/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.1633A>G	p.Ile545Val	missense_variant	18/22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1088061 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 353849

Gnomad4 AFR exome AF: 0.0000381

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.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 07, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.68	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L;L;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.89	N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.22
Sift	Benign	0.064	T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.11	T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.72	P;P;B;B;B;B;B;.;B;B;B;P
Vest4		0.42
MutPred		0.71		Gain of ubiquitination at K541 (P = 0.1181);Gain of ubiquitination at K541 (P = 0.1181);.;.;.;.;.;.;.;.;.;.;
MVP		0.81
MPC		1.3
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.49
gMVP		0.80

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: rs1555927575; hg19: chrX-20183148;