11-64360289-A-C

Position:

• chr11-64360289-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003942.3(RPS6KA4):​c.254A>C​(p.Glu85Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KA4	NM_003942.3	c.254A>C	p.Glu85Ala	missense_variant	3/17	ENST00000334205.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KA4	ENST00000334205.9	c.254A>C	p.Glu85Ala	missense_variant	3/17	1	NM_003942.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.254A>C (p.E85A) alteration is located in exon 3 (coding exon 3) of the RPS6KA4 gene. This alteration results from a A to C substitution at nucleotide position 254, causing the glutamic acid (E) at amino acid position 85 to be replaced by an alanine (A). 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	0.99
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.074	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.70
MutPred		0.91		Gain of MoRF binding (P = 0.0113);Gain of MoRF binding (P = 0.0113);.;
MVP		0.95
MPC		2.7
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.89
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64127761;