NM_004586.3:c.2118A>G

Variant names:

• chrX-20155503-T-C
• rs760969945
• NM_004586.3:c.2118A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_004586.3(RPS6KA3):​c.2118A>G​(p.Thr706Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,851 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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 0.000018 (0 hom., 1 hem., cov: 22)
• Consequence: RPS6KA3 NM_004586.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.777
• 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_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-20155503-T-C is Benign according to our data. Variant chrX-20155503-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2930243.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.777 with no splicing effect.

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.2118A>G	p.Thr706Thr	synonymous	Exon 22 of 22	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.2034A>G	p.Thr678Thr	synonymous	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.2118A>G	p.Thr706Thr	synonymous	Exon 22 of 22	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.2166A>G	p.Thr722Thr	synonymous	Exon 23 of 23	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.2136A>G	p.Thr712Thr	synonymous	Exon 22 of 22	ENSP00000586352.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111797 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 29

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111851 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 34047

African (AFR) AF: 0.00 AC: 0 AN: 30802

American (AMR) AF: 0.0000954 AC: 1 AN: 10484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6063

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53193

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.7
DANN	Benign	0.56
PhyloP100		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs760969945; hg19: chrX-20173621;