X-20155424-TA-T

Variant names:

• chrX-20155424-TA-T
• rs1603417191
• NM_004586.3:c.2196delT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_004586.3(RPS6KA3):​c.2196delT​(p.Ile735SerfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPS6KA3 NM_004586.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.557
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet, Genomics England PanelApp
• 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_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0121 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-20155424-TA-T is Pathogenic according to our data. Variant chrX-20155424-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 635336.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2196delT	p.Ile735SerfsTer66	frameshift	Exon 22 of 22	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.2112delT	p.Ile707SerfsTer66	frameshift	Exon 22 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.2196delT	p.Ile735SerfsTer66	frameshift	Exon 22 of 22	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.2244delT	p.Ile751SerfsTer66	frameshift	Exon 23 of 23	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.2214delT	p.Ile741SerfsTer66	frameshift	Exon 22 of 22	ENSP00000586352.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Coffin-Lowry syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs1603417191; hg19: chrX-20173542;