RPS6KA4 p.Glu249Asp

Variant names:

• chr11-64361737-G-T
• NM_003942.3:c.747G>T
• RPS6KA4 p.Glu249Asp

Your query was ambiguous. Multiple possible variants found:

• chr11-64361737-G-T
• chr11-64361737-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003942.3(RPS6KA4):​c.747G>T​(p.Glu249Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.70
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1923638).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003942.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA4	NM_003942.3	MANE Select	c.747G>T	p.Glu249Asp	missense	Exon 7 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.747G>T	p.Glu249Asp	missense	Exon 7 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.747G>T	p.Glu249Asp	missense	Exon 7 of 17	NP_001287731.1	E9PJN1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KA4	ENST00000334205.9	TSL:1 MANE Select	c.747G>T	p.Glu249Asp	missense	Exon 7 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.747G>T	p.Glu249Asp	missense	Exon 7 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.906G>T	p.Glu302Asp	missense	Exon 7 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.80	N
PhyloP100		1.7
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.051
Sift	Benign	0.20	T
Sift4G	Benign	0.22	T
Varity_R		0.097
gMVP		0.63
Mutation Taster		=82/18	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-64129209;