NM_003942.3:c.259T>G

Variant names:

• chr11-64360294-T-G
• NM_003942.3:c.259T>G

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.259T>G​(p.Ser87Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,395,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.806
• 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=0.15509292).

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.259T>G	p.Ser87Ala	missense	Exon 3 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.259T>G	p.Ser87Ala	missense	Exon 3 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.259T>G	p.Ser87Ala	missense	Exon 3 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.259T>G	p.Ser87Ala	missense	Exon 3 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.259T>G	p.Ser87Ala	missense	Exon 3 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.259T>G	p.Ser87Ala	missense	Exon 3 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395702 Hom.: 0 Cov.: 53 AF XY: 0.00000436 AC XY: 3 AN XY: 688340

African (AFR) AF: 0.00 AC: 0 AN: 31538

American (AMR) AF: 0.00 AC: 0 AN: 35644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25154

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078218

Other (OTH) AF: 0.00 AC: 0 AN: 57844

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.81
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.086
Sift	Benign	0.14	T
Sift4G	Benign	0.10	T
Polyphen		0.14	B
Vest4		0.21
MutPred		0.47		Loss of disorder (P = 0.0557)
MVP		0.62
MPC		1.2
ClinPred		0.093	T
GERP RS		2.9
Varity_R		0.24
gMVP		0.71
Mutation Taster		=94/6	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

Other links and lift over

hg19: chr11-64127766;