11-64361956-C-T

Variant names:

• chr11-64361956-C-T
• rs61736650
• NM_003942.3:c.860C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003942.3(RPS6KA4):​c.860C>T​(p.Ala287Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,610,484 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: RPS6KA4 NM_003942.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.30
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00985986).
• BP6: Variant 11-64361956-C-T is Benign according to our data. Variant chr11-64361956-C-T is described in ClinVar as Benign. ClinVar VariationId is 787911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 543 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.860C>T	p.Ala287Val	missense	Exon 8 of 17	NP_003933.1	O75676-1
	RPS6KA4	NM_001006944.2		c.860C>T	p.Ala287Val	missense	Exon 8 of 17	NP_001006945.1	O75676-2
	RPS6KA4	NM_001300802.2		c.860C>T	p.Ala287Val	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.860C>T	p.Ala287Val	missense	Exon 8 of 17	ENSP00000333896.4	O75676-1
	RPS6KA4	ENST00000528057.5	TSL:1	c.860C>T	p.Ala287Val	missense	Exon 8 of 17	ENSP00000435580.1	E9PJN1
	RPS6KA4	ENST00000969972.1		c.1019C>T	p.Ala340Val	missense	Exon 8 of 17	ENSP00000640031.1

Frequencies

GnomAD3 genomes AF: 0.00356 AC: 541 AN: 152130 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00101 AC: 249 AN: 247400 AF XY: 0.000730

Gnomad AFR exome AF: 0.0144

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000422 AC: 615 AN: 1458236 Hom.: 4 Cov.: 32 AF XY: 0.000357 AC XY: 259 AN XY: 725650

African (AFR) AF: 0.0156 AC: 516 AN: 33164

American (AMR) AF: 0.000436 AC: 19 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25978

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1111008

Other (OTH) AF: 0.000797 AC: 48 AN: 60248

GnomAD4 genome AF: 0.00357 AC: 543 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74424

African (AFR) AF: 0.0126 AC: 525 AN: 41538

American (AMR) AF: 0.000458 AC: 7 AN: 15300

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68008

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00198 Hom.: 3

Bravo AF: 0.00458

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0134 AC: 59

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.00079
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.3
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Uncertain	0.010	D
Sift4G	Benign	0.11	T
Polyphen		0.061	B
Vest4		0.32
MVP		0.47
MPC		0.47
ClinPred		0.030	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.57
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61736650; hg19: chr11-64129428; COSMIC: COSV53705642;