X-20234770-AAT-TGA

Variant names:

• chrX-20234770-AAT-TGA
• NM_004586.3:c.112_114delATTinsTCA
• RPS6KA3 p.Ile38Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_004586.3(RPS6KA3):​c.112_114delATTinsTCA​(p.Ile38Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 22)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70
• 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: ClinGen, Orphanet, G2P, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 11 curated benign missense variants. Gene score misZ: 4.5208 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to symptomatic form of Coffin-Lowry syndrome in female carriers, non-syndromic X-linked intellectual disability, Coffin-Lowry syndrome, intellectual disability, X-linked 19.

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.112_114delATTinsTCA	p.Ile38Ser	missense	N/A	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.28_30delATTinsTCA	p.Ile10Ser	missense	N/A	NP_001425269.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.112_114delATTinsTCA	p.Ile38Ser	missense	N/A	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.112_114delATTinsTCA	p.Ile38Ser	missense	N/A	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.112_114delATTinsTCA	p.Ile38Ser	missense	N/A	ENSP00000586352.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-20252888;