chrX-20155416-G-A

Variant names:

• chrX-20155416-G-A
• rs371053039
• NM_004586.3:c.2205C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_004586.3(RPS6KA3):​c.2205C>T​(p.Ile735Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,208,399 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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)
  • Exomes 𝑓: 0.000013 (0 hom. 5 hem.)
• Consequence: RPS6KA3 NM_004586.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.29
• 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant X-20155416-G-A is Benign according to our data. Variant chrX-20155416-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2057737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=3.29 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 14 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.2205C>T	p.Ile735Ile	synonymous	Exon 22 of 22	NP_004577.1	P51812
	RPS6KA3	NM_001438340.1		c.2121C>T	p.Ile707Ile	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.2205C>T	p.Ile735Ile	synonymous	Exon 22 of 22	ENSP00000368884.3	P51812
	RPS6KA3	ENST00000952699.1		c.2253C>T	p.Ile751Ile	synonymous	Exon 23 of 23	ENSP00000622758.1
	RPS6KA3	ENST00000916293.1		c.2223C>T	p.Ile741Ile	synonymous	Exon 22 of 22	ENSP00000586352.1

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110622 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000274 AC: 5 AN: 182500 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097777 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 5 AN XY: 363145

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 841722

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110622 Hom.: 0 Cov.: 22 AF XY: 0.0000305 AC XY: 1 AN XY: 32834

African (AFR) AF: 0.00 AC: 0 AN: 30373

American (AMR) AF: 0.00 AC: 0 AN: 10292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2605

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52935

Other (OTH) AF: 0.00 AC: 0 AN: 1477

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

EpiCase AF: 0.000273

EpiControl AF: 0.00

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)
-	-	1	RPS6KA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs371053039; hg19: chrX-20173534;