rs144984628

Variant names:

• chrX-20155453-C-T
• rs144984628
• NM_004586.3:c.2168G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_004586.3(RPS6KA3):​c.2168G>A​(p.Arg723His) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,208,024 control chromosomes in the GnomAD database, including 3 homozygotes. There are 471 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R723C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., 44 hem., cov: 22)
  • Exomes 𝑓: 0.0013 (3 hom. 427 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:10
• Conservation: PhyloP100: 3.80
• Publications: 2 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: Benign. The variant received -15 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, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, intellectual disability, X-linked 19.
• BP4: Computational evidence support a benign effect (MetaRNN=0.008939147).
• BP6: Variant X-20155453-C-T is Benign according to our data. Variant chrX-20155453-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 140 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	NM_004586.3	MANE Select	c.2168G>A	p.Arg723His	missense	Exon 22 of 22	NP_004577.1
	RPS6KA3	NM_001438340.1		c.2084G>A	p.Arg695His	missense	Exon 22 of 22	NP_001425269.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA3	ENST00000379565.9	TSL:1 MANE Select	c.2168G>A	p.Arg723His	missense	Exon 22 of 22	ENSP00000368884.3
	RPS6KA3	ENST00000642835.1		c.2084G>A	p.Arg695His	missense	Exon 25 of 25	ENSP00000494769.1
	RPS6KA3	ENST00000643085.1		c.2084G>A	p.Arg695His	missense	Exon 24 of 24	ENSP00000496271.1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 140 AN: 111111 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000983

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: 0.00895

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00151 AC: 275 AN: 181908 AF XY: 0.00131

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00129 AC: 1410 AN: 1096857 Hom.: 3 Cov.: 29 AF XY: 0.00118 AC XY: 427 AN XY: 362239

African (AFR) AF: 0.000152 AC: 4 AN: 26369

American (AMR) AF: 0.0000284 AC: 1 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.0000516 AC: 1 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.00 AC: 0 AN: 54115

European-Finnish (FIN) AF: 0.00999 AC: 405 AN: 40530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00113 AC: 954 AN: 840873

Other (OTH) AF: 0.000977 AC: 45 AN: 46064

GnomAD4 genome AF: 0.00126 AC: 140 AN: 111167 Hom.: 0 Cov.: 22 AF XY: 0.00132 AC XY: 44 AN XY: 33389

African (AFR) AF: 0.0000980 AC: 3 AN: 30602

American (AMR) AF: 0.00 AC: 0 AN: 10376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3566

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00895 AC: 53 AN: 5920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00158 AC: 84 AN: 53040

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00103 Hom.: 43

Bravo AF: 0.000654

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.00129 AC: 157

EpiCase AF: 0.00125

EpiControl AF: 0.000711

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Coffin-Lowry syndrome (1)
-	-	1	Coffin-Lowry syndrome;C0796225:Intellectual disability, X-linked 19 (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
-	-	1	Intellectual disability, X-linked 19 (1)
-	-	1	RPS6KA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.24
Sift	Benign	0.047	D
Sift4G	Benign	0.10	T
Polyphen		0.38	B
Vest4		0.74
MVP		0.91
MPC		2.1
ClinPred		0.016	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.58
Mutation Taster		=90/10	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: rs144984628; hg19: chrX-20173571;