rs868745357

Variant names:

• chr11-64369458-C-G
• rs868745357
• NM_003942.3:c.1441C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-64369458-C-G
• chr11-64369458-C-T

Variant summary

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

The NM_003942.3(RPS6KA4):​c.1441C>G​(p.Leu481Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,606,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1441C>G	p.Leu481Val	missense	Exon 13 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.1423C>G	p.Leu475Val	missense	Exon 13 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.1420C>G	p.Leu474Val	missense	Exon 13 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.1441C>G	p.Leu481Val	missense	Exon 13 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.1420C>G	p.Leu474Val	missense	Exon 13 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.1600C>G	p.Leu534Val	missense	Exon 13 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1453856 Hom.: 0 Cov.: 34 AF XY: 0.00000553 AC XY: 4 AN XY: 723096

African (AFR) AF: 0.0000300 AC: 1 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85640

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5432

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110146

Other (OTH) AF: 0.0000333 AC: 2 AN: 60020

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Asia WGS AF: 0.000867 AC: 3 AN: 3476

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	0.12
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.23
Sift	Benign	0.12	T
Sift4G	Uncertain	0.042	D
Polyphen		0.95	P
Vest4		0.53
MutPred		0.77		Loss of sheet (P = 0.302)
MVP		0.54
MPC		1.6
ClinPred		0.83	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.11
gMVP		0.93
Mutation Taster		=45/55	disease causing

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: rs868745357; hg19: chr11-64136930;