rs1555931252

Positions:

• chrX-20172765-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_004586.3(RPS6KA3):​c.1334A>G​(p.Asn445Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,088,819 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29

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 -3 ACMG points.

• PM1: In a domain Protein kinase 2 (size 257) in uniprot entity KS6A3_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_004586.3
• PP2: Missense variant where missense usually causes diseases, RPS6KA3
• BP4: Computational evidence support a benign effect (MetaRNN=0.19616008).
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3	c.1334A>G	p.Asn445Ser	missense_variant	15/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.1334A>G	p.Asn445Ser	missense_variant	15/22	1	NM_004586.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000551 AC: 6 AN: 1088819 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 355985

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: 0.00000598

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 23, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.055
Sift	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.28	T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;B;B;B;B;B;B;.;B;B;B;B
Vest4		0.13
MutPred		0.39		Gain of MoRF binding (P = 0.1488);Gain of MoRF binding (P = 0.1488);.;.;.;.;.;.;.;.;.;.;
MVP		0.61
MPC		1.2
ClinPred		0.47	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.15

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: rs1555931252; hg19: chrX-20190883;