rs111948591

Variant names:

• chrX-20155892-C-T
• rs111948591
• NM_004586.3:c.2100+217G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004586.3(RPS6KA3):​c.2100+217G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0127 in 112,305 control chromosomes in the GnomAD database, including 9 homozygotes. There are 439 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 0.013 (9 hom., 439 hem., cov: 22)
• Consequence: RPS6KA3 NM_004586.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0720
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant X-20155892-C-T is Benign according to our data. Variant chrX-20155892-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1193963.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 1421 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.2100+217G>A		intron	N/A	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.2016+217G>A		intron	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.2100+217G>A		intron	N/A	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.2148+217G>A		intron	N/A	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.2118+217G>A		intron	N/A	ENSP00000586352.1

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1412 AN: 112254 Hom.: 9 Cov.: 22

Gnomad AFR AF: 0.00901

Gnomad AMI AF: 0.0533

Gnomad AMR AF: 0.0153

Gnomad ASJ AF: 0.0491

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00587

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0185

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

GnomAD4 genome AF: 0.0127 AC: 1421 AN: 112305 Hom.: 9 Cov.: 22 AF XY: 0.0127 AC XY: 439 AN XY: 34485

African (AFR) AF: 0.00928 AC: 287 AN: 30929

American (AMR) AF: 0.0153 AC: 162 AN: 10614

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 130 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.00626 AC: 17 AN: 2716

European-Finnish (FIN) AF: 0.00490 AC: 30 AN: 6123

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.0137 AC: 728 AN: 53248

Other (OTH) AF: 0.0182 AC: 28 AN: 1535

Alfa AF: 0.0122 Hom.: 56

Bravo AF: 0.0150

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		0.072
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: rs111948591; hg19: chrX-20174010;