rs56338023

Variant names:

• chrX-20209318-T-C
• rs56338023
• NM_004586.3:c.213A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_004586.3(RPS6KA3):​c.213A>G​(p.Leu71Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,190,051 control chromosomes in the GnomAD database, including 8 homozygotes. There are 1,513 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., 106 hem., cov: 23)
  • Exomes 𝑓: 0.0042 (7 hom. 1407 hem.)
• Consequence: RPS6KA3 NM_004586.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0450
• Publications: 2 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: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-20209318-T-C is Benign according to our data. Variant chrX-20209318-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212069.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.045 with no splicing effect.
• BS2: High AC in GnomAd4 at 364 AD,XL gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	NM_004586.3	MANE Select	c.213A>G	p.Leu71Leu	synonymous	Exon 3 of 22	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.129A>G	p.Leu43Leu	synonymous	Exon 3 of 22	NP_001425269.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.213A>G	p.Leu71Leu	synonymous	Exon 3 of 22	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.213A>G	p.Leu71Leu	synonymous	Exon 3 of 23	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.213A>G	p.Leu71Leu	synonymous	Exon 3 of 22	ENSP00000586352.1

Frequencies

GnomAD3 genomes AF: 0.00326 AC: 364 AN: 111751 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000455

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000759

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00766

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00531

Gnomad OTH AF: 0.00263

GnomAD2 exomes AF: 0.00359 AC: 658 AN: 183190 AF XY: 0.00359

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00785

Gnomad NFE exome AF: 0.00572

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00417 AC: 4496 AN: 1078248 Hom.: 7 Cov.: 26 AF XY: 0.00406 AC XY: 1407 AN XY: 346422

African (AFR) AF: 0.000692 AC: 18 AN: 26008

American (AMR) AF: 0.000512 AC: 18 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 30 AN: 19254

East Asian (EAS) AF: 0.00 AC: 0 AN: 30088

South Asian (SAS) AF: 0.00140 AC: 75 AN: 53688

European-Finnish (FIN) AF: 0.00705 AC: 285 AN: 40447

Middle Eastern (MID) AF: 0.000763 AC: 3 AN: 3932

European-Non Finnish (NFE) AF: 0.00477 AC: 3928 AN: 824188

Other (OTH) AF: 0.00306 AC: 139 AN: 45465

GnomAD4 genome AF: 0.00326 AC: 364 AN: 111803 Hom.: 1 Cov.: 23 AF XY: 0.00312 AC XY: 106 AN XY: 33975

African (AFR) AF: 0.000454 AC: 14 AN: 30846

American (AMR) AF: 0.000758 AC: 8 AN: 10554

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2641

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3576

South Asian (SAS) AF: 0.00113 AC: 3 AN: 2663

European-Finnish (FIN) AF: 0.00766 AC: 46 AN: 6009

Middle Eastern (MID) AF: 0.00463 AC: 1 AN: 216

European-Non Finnish (NFE) AF: 0.00531 AC: 282 AN: 53072

Other (OTH) AF: 0.00260 AC: 4 AN: 1539

Alfa AF: 0.00453 Hom.: 31

Bravo AF: 0.00246

EpiCase AF: 0.00447

EpiControl AF: 0.00279

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	RPS6KA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	9.4
DANN	Benign	0.85
PhyloP100		-0.045
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs56338023; hg19: chrX-20227436; COSMIC: COSV65389472;