rs1555950495

Variant names:

• chrX-20209306-C-A
• rs1555950495
• NM_004586.3:c.225G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_004586.3(RPS6KA3):​c.225G>T​(p.Gly75Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,049,928 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: RPS6KA3 NM_004586.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.390
• Publications: 0 publications found

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]

RPS6KA3 Gene-Disease associations (from GenCC):

• Coffin-Lowry syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, G2P
• intellectual disability, X-linked 19

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• symptomatic form of Coffin-Lowry syndrome in female carriers

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant X-20209306-C-A is Benign according to our data. Variant chrX-20209306-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 436559.
• BP7: Synonymous conserved (PhyloP=-0.39 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004586.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	NM_004586.3	MANE Select	c.225G>T	p.Gly75Gly	synonymous	Exon 3 of 22	NP_004577.1
	RPS6KA3	NM_001438340.1		c.141G>T	p.Gly47Gly	synonymous	Exon 3 of 22	NP_001425269.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.225G>T	p.Gly75Gly	synonymous	Exon 3 of 22	ENSP00000368884.3
	RPS6KA3	ENST00000642835.1		c.141G>T	p.Gly47Gly	synonymous	Exon 6 of 25	ENSP00000494769.1
	RPS6KA3	ENST00000643085.1		c.141G>T	p.Gly47Gly	synonymous	Exon 5 of 24	ENSP00000496271.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000381 AC: 4 AN: 1049928 Hom.: 0 Cov.: 24 AF XY: 0.00000306 AC XY: 1 AN XY: 326382

African (AFR) AF: 0.00 AC: 0 AN: 25405

American (AMR) AF: 0.00 AC: 0 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19087

East Asian (EAS) AF: 0.0000334 AC: 1 AN: 29947

South Asian (SAS) AF: 0.00 AC: 0 AN: 53083

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40419

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3790

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 798557

Other (OTH) AF: 0.0000674 AC: 3 AN: 44497

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 (1)
-	1	-	not specified (1)
-	-	1	RPS6KA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	7.6
DANN	Benign	0.68
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1555950495; hg19: chrX-20227424;