11-64359256-T-A

Variant names:

• chr11-64359256-T-A
• rs1192359059
• NM_003942.3:c.21T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003942.3(RPS6KA4):​c.21T>A​(p.Asp7Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,306,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03573993).

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.21T>A	p.Asp7Glu	missense	Exon 1 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.21T>A	p.Asp7Glu	missense	Exon 1 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.21T>A	p.Asp7Glu	missense	Exon 1 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.21T>A	p.Asp7Glu	missense	Exon 1 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.21T>A	p.Asp7Glu	missense	Exon 1 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.21T>A	p.Asp7Glu	missense	Exon 1 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.65e-7 AC: 1 AN: 1306464 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 638286

African (AFR) AF: 0.00 AC: 0 AN: 27574

American (AMR) AF: 0.00 AC: 0 AN: 26080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20628

East Asian (EAS) AF: 0.00 AC: 0 AN: 30540

South Asian (SAS) AF: 0.00 AC: 0 AN: 67882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5190

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1028484

Other (OTH) AF: 0.0000188 AC: 1 AN: 53288

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.93
DEOGEN2	Benign	0.051	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-1.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.048
Sift	Benign	0.67	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.028
MutPred		0.30		Gain of glycosylation at S9 (P = 0.1037)
MVP		0.37
MPC		1.3
ClinPred		0.091	T
GERP RS		-7.2
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.048
gMVP		0.73
Mutation Taster		=90/10	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

dbSNP: rs1192359059; hg19: chr11-64126728;