rs1555931252

Variant names:

• chrX-20172765-T-C
• rs1555931252
• NM_004586.3:c.1334A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1 PP2 BP4_Moderate BS2

The NM_004586.3(RPS6KA3):​c.1334A>G​(p.Asn445Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000551 in 1,088,819 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 4 hem.)
• Consequence: RPS6KA3 NM_004586.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U: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: 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_benign. The variant received -3 ACMG points.

• PM1: In a domain Protein kinase 2 (size 257) in uniprot entity KS6A3_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_004586.3
• 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=0.19616008).
• BS2: High AC in GnomAdExome4 at 6 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA3	NM_004586.3	c.1334A>G	p.Asn445Ser	missense_variant	Exon 15 of 22	ENST00000379565.9	NP_004577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA3	ENST00000379565.9	c.1334A>G	p.Asn445Ser	missense_variant	Exon 15 of 22	1	NM_004586.3	ENSP00000368884.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000551 AC: 6 AN: 1088819 Hom.: 0 Cov.: 28 AF XY: 0.0000112 AC XY: 4 AN XY: 355985

African (AFR) AF: 0.00 AC: 0 AN: 26229

American (AMR) AF: 0.00 AC: 0 AN: 34575

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19190

East Asian (EAS) AF: 0.00 AC: 0 AN: 29991

South Asian (SAS) AF: 0.00 AC: 0 AN: 53345

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40187

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4088

European-Non Finnish (NFE) AF: 0.00000598 AC: 5 AN: 835542

Other (OTH) AF: 0.0000219 AC: 1 AN: 45672

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1334A>G (p.N445S) alteration is located in exon 15 (coding exon 15) of the RPS6KA3 gene. This alteration results from a A to G substitution at nucleotide position 1334, causing the asparagine (N) at amino acid position 445 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;.;.;.;.;.;.;.;.;.;T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	.;D;.;.;.;.;.;D;.;.;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.055
Sift	Benign	0.37	T;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.28	T;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0010	B;B;B;B;B;B;B;.;B;B;B;B
Vest4		0.13
MutPred		0.39		Gain of MoRF binding (P = 0.1488);Gain of MoRF binding (P = 0.1488);.;.;.;.;.;.;.;.;.;.;
MVP		0.61
MPC		1.2
ClinPred		0.47	T
GERP RS		3.9
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.15
Mutation Taster		=93/7	polymorphism

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: rs1555931252; hg19: chrX-20190883;