Genetic Variant RPS6KA4:p.Thr336Ile (chr11-64365401-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003942.3(RPS6KA4):c.1007C>T(p.Thr336Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RPS6KA4
NM_003942.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

RPS6KA4 (HGNC:10433): (ribosomal protein S6 kinase A4) 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 CREB1 and ATF1. The encoded protein can also phosphorylate histone H3 to regulate certain inflammatory genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

RPS6KA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA4	NM_003942.3 link	c.1007C>T	p.Thr336Ile	missense_variant	Exon 9 of 17	ENST00000334205.9	NP_003933.1	O75676-1A0PJF8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KA4	ENST00000334205.9 link	c.1007C>T	p.Thr336Ile	missense_variant	Exon 9 of 17	1	NM_003942.3	ENSP00000333896.4		O75676-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251152

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000123

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44722

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000116

AC:

AN:

86250

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53334

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1111978

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

60394

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1007C>T (p.T336I) alteration is located in exon 9 (coding exon 9) of the RPS6KA4 gene. This alteration results from a C to T substitution at nucleotide position 1007, causing the threonine (T) at amino acid position 336 to be replaced by an isoleucine (I). 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

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.40

MutationAssessor

Pathogenic

3.3

.;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-5.7

D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.85

MVP

0.75

MPC

1.3

ClinPred

0.99

GERP RS

4.9

Varity_R

0.80

gMVP

0.88

Mutation Taster

=26/74

disease causing

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