X-20195143-G-C

Variant names:

• chrX-20195143-G-C
• rs1555943484
• NM_004586.3:c.328C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_004586.3(RPS6KA3):​c.328C>G​(p.Arg110Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000965 in 1,036,250 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.7e-7 (0 hom. 1 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.44
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a domain Protein kinase 1 (size 259) in uniprot entity KS6A3_HUMAN there are 27 pathogenic changes around while only 1 benign (96%) in NM_004586.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.328C>G	p.Arg110Gly	missense_variant, splice_region_variant	Exon 5 of 22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.328C>G	p.Arg110Gly	missense_variant, splice_region_variant	Exon 5 of 22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.65e-7 AC: 1 AN: 1036250 Hom.: 0 Cov.: 22 AF XY: 0.00000320 AC XY: 1 AN XY: 312152

African (AFR) AF: 0.00 AC: 0 AN: 25214

American (AMR) AF: 0.00 AC: 0 AN: 35074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18921

East Asian (EAS) AF: 0.00 AC: 0 AN: 29876

South Asian (SAS) AF: 0.00 AC: 0 AN: 52568

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40409

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3972

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 786193

Other (OTH) AF: 0.0000227 AC: 1 AN: 44023

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.;.;.;.;.;T;.;.;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.58	N;N;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D;.;.;.;.;.;.;D;.;.;.;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.99	D;D;D;D;D;D;D;.;D;D;D;P
Vest4		0.64
MutPred		0.55		Loss of stability (P = 0.0455);Loss of stability (P = 0.0455);.;.;.;.;.;.;.;.;.;.;
MVP		0.95
MPC		2.8
ClinPred		0.98	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.99
gMVP		0.98
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555943484; hg19: chrX-20213261;