NM_003942.3:c.806C>T

Variant names:

• chr11-64361902-C-T
• rs142374327
• NM_003942.3:c.806C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003942.3(RPS6KA4):​c.806C>T​(p.Ala269Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11001697).
• BS2: High AC in GnomAd4 at 42 AD gene.

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.806C>T	p.Ala269Val	missense	Exon 8 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.806C>T	p.Ala269Val	missense	Exon 8 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.806C>T	p.Ala269Val	missense	Exon 8 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.806C>T	p.Ala269Val	missense	Exon 8 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.806C>T	p.Ala269Val	missense	Exon 8 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.965C>T	p.Ala322Val	missense	Exon 8 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249554 AF XY: 0.0000443

Gnomad AFR exome AF: 0.000632

Gnomad AMR exome AF: 0.0000579

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: 0.0000260 AC: 38 AN: 1460760 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 726722

African (AFR) AF: 0.000747 AC: 25 AN: 33462

American (AMR) AF: 0.0000448 AC: 2 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74404

African (AFR) AF: 0.00101 AC: 42 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000289 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

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	0.26
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.20	N
REVEL	Uncertain	0.29
Sift	Benign	0.18	T
Sift4G	Benign	0.28	T
Polyphen		0.98	D
Vest4		0.72
MVP		0.61
MPC		0.48
ClinPred		0.045	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.71
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

dbSNP: rs142374327; hg19: chr11-64129374; COSMIC: COSV53702327; COSMIC: COSV53702327;