Variant X-20155454-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_ModerateBP6_Moderate

The NM_004586.3(RPS6KA3):c.2167C>T(p.Arg723Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,096,753 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R723H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

RPS6KA3
NM_004586.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.71

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPS6KA3. . Gene score misZ 4.5208 (greater than the threshold 3.09). GenCC has associacion of gene with intellectual disability, X-linked 19, Coffin-Lowry syndrome, non-syndromic X-linked intellectual disability, symptomatic form of Coffin-Lowry syndrome in female carriers.

BP4

Computational evidence support a benign effect (MetaRNN=0.16443244).

BP6

Variant X-20155454-G-A is Benign according to our data. Variant chrX-20155454-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3156209.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA3	NM_004586.3 linkuse as main transcript	c.2167C>T	p.Arg723Cys	missense_variant	22/22	ENST00000379565.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA3	ENST00000379565.9 linkuse as main transcript	c.2167C>T	p.Arg723Cys	missense_variant	22/22	1	NM_004586.3	P4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1096753

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362137

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000331

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T;.;.;.;.;.;.;.;.;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.95

.;D;.;.;.;.;.;D;.;.;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.16

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.9

N;N;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.020

N;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.15

Sift

Benign

0.092

T;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.12

T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.0

B;B;B;B;B;B;B;.;B;B;B;B

Vest4

0.16

MutPred

0.32

Loss of MoRF binding (P = 0.0025);Loss of MoRF binding (P = 0.0025);.;.;.;.;.;.;.;.;.;.;

MVP

0.55

MPC

1.9

ClinPred

0.51

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over