rs1192359059

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr11-64359256-T-G
• chr11-64359256-T-A
• chr11-64359256-T-C

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>G​(p.Asp7Glu) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000046 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.68
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03545153).

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000459 AC: 6 AN: 1306394 Hom.: 0 Cov.: 31 AF XY: 0.00000627 AC XY: 4 AN XY: 638250

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00000583 AC: 6 AN: 1028414

Other (OTH) AF: 0.00 AC: 0 AN: 53288

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00317486), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.066
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	0.15	N
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.035	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	0.049
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		0.36
MPC		1.3
ClinPred		0.077	T
GERP RS		-7.2
PromoterAI		0.056	Neutral
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;