Genetic Variant RPS6KA4:p.Cys590Cys (chr11-64369866-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_003942.3(RPS6KA4):c.1770C>T(p.Cys590Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,560,258 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0071 ( 15 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 33 hom. )

Consequence

RPS6KA4
NM_003942.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.45

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 11-64369866-C-T is Benign according to our data. Variant chr11-64369866-C-T is described in ClinVar as [Benign]. Clinvar id is 776621.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-1.45 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00708 (1079/152300) while in subpopulation AFR AF= 0.0243 (1009/41568). AF 95% confidence interval is 0.023. There are 15 homozygotes in gnomad4. There are 489 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1079 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KA4	NM_003942.3 link	c.1770C>T	p.Cys590Cys	synonymous_variant	Exon 14 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.1770C>T	p.Cys590Cys	synonymous_variant	Exon 14 of 17	1	NM_003942.3	ENSP00000333896.4		O75676-1

Frequencies

GnomAD3 genomes

AF:

0.00706

AC:

1074

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00288

AC:

460

AN:

159514

Hom.:

AF XY:

0.00294

AC XY:

252

AN XY:

85720

show subpopulations

Gnomad AFR exome

AF:

0.0249

Gnomad AMR exome

AF:

0.00147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00803

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000489

Gnomad OTH exome

AF:

0.000913

GnomAD4 exome

AF:

0.00128

AC:

1805

AN:

1407958

Hom.:

Cov.:

AF XY:

0.00140

AC XY:

976

AN XY:

695862

show subpopulations

Gnomad4 AFR exome

AF:

0.0282

Gnomad4 AMR exome

AF:

0.00147

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000274

Gnomad4 SAS exome

AF:

0.00833

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000184

Gnomad4 OTH exome

AF:

0.00256

GnomAD4 genome

AF:

0.00708

AC:

1079

AN:

152300

Hom.:

Cov.:

AF XY:

0.00657

AC XY:

489

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0243

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00642

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00753

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.6

DANN

Benign

0.93

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

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