X-20155519-C-T

Variant summary

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

The NM_004586.3(RPS6KA3):c.2102G>A(p.Gly701Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: RPS6KA3 NM_004586.3 missense, splice_region
• Scores: Splicing: ADA: 0.01454
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.81

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 where missense usually causes diseases, RPS6KA3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3	c.2102G>A	p.Gly701Asp	missense_variant, splice_region_variant	22/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.2102G>A	p.Gly701Asp	missense_variant, splice_region_variant	22/22	1	NM_004586.3	P4

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 30, 2021

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D;D;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;M;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-3.8	D;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.11	T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.041	B;B;D;D;D;D;D;.;D;D;D;B
Vest4		0.64
MutPred		0.43		Loss of methylation at K700 (P = 0.0947);Loss of methylation at K700 (P = 0.0947);.;.;.;.;.;.;.;.;.;.;
MVP		0.81
MPC		2.8
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.12
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-20173637;