X-20155459-A-C

Position:

• chrX-20155459-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_004586.3(RPS6KA3):​c.2162T>G​(p.Val721Gly) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 5 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, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.2162T>G	p.Val721Gly	missense_variant	22/22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.2162T>G	p.Val721Gly	missense_variant	22/22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PP3_Moderate+PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;D;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.9	D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.98	D;D;D;D;D;D;D;.;D;D;D;D
Vest4		0.59
MutPred		0.47		Loss of stability (P = 0.013);Loss of stability (P = 0.013);.;.;.;.;.;.;.;.;.;.;
MVP		0.95
MPC		3.2
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.95
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-20173577;