chrX-20195156-T-C

Variant names:

• chrX-20195156-T-C
• rs1555943503
• NM_004586.3:c.326-11A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004586.3(RPS6KA3):​c.326-11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: RPS6KA3 NM_004586.3 intron
• Scores: Splicing: ADA: 0.9382
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.336
• 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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant X-20195156-T-C is Pathogenic according to our data. Variant chrX-20195156-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.326-11A>G		intron_variant	Intron 4 of 21	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.326-11A>G		intron_variant	Intron 4 of 21	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 18

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Coffin-Lowry syndrome Pathogenic:2

Jun 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Aug 16, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the literature in a patient with features of RPS6KA3-Related Coffin-Lowry Spectrum Disorder and functional studies demonstrate that this non-canonical splice site variant resulted in loss-of-function (PMID:11992250); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11992250) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.1
DANN	Benign	0.38
PhyloP100		-0.34
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -1
DS_AL_spliceai		0.70		Position offset: -11

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

Other links and lift over

dbSNP: rs1555943503; hg19: chrX-20213274;