chr14-74909654-C-T

Variant names:

• chr14-74909654-C-T
• rs374989083
• NM_031464.5:c.1159G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031464.5(RPS6KL1):​c.1159G>A​(p.Glu387Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,610,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: RPS6KL1 NM_031464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

Genes affected

RPS6KL1 (HGNC:20222): (ribosomal protein S6 kinase like 1) Predicted to enable ATP binding activity; protein serine kinase activity; and protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation. Predicted to be located in ribosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2484869).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031464.5. 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
	RPS6KL1	NM_031464.5	MANE Select	c.1159G>A	p.Glu387Lys	missense	Exon 8 of 12	NP_113652.2	Q9Y6S9-1
	RPS6KL1	NM_001370252.1		c.1159G>A	p.Glu387Lys	missense	Exon 7 of 11	NP_001357181.1
	RPS6KL1	NM_001370253.1		c.1114G>A	p.Glu372Lys	missense	Exon 8 of 11	NP_001357182.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KL1	ENST00000557413.6	TSL:5 MANE Select	c.1159G>A	p.Glu387Lys	missense	Exon 8 of 12	ENSP00000450567.1	Q9Y6S9-1
	RPS6KL1	ENST00000555009.5	TSL:1	n.1066G>A		non_coding_transcript_exon	Exon 6 of 12	ENSP00000450660.1	Q9Y6S9-2
	RPS6KL1	ENST00000961459.1		c.1207G>A	p.Glu403Lys	missense	Exon 9 of 13	ENSP00000631518.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000326 AC: 8 AN: 245094 AF XY: 0.0000299

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000542

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000466 AC: 68 AN: 1458592 Hom.: 0 Cov.: 32 AF XY: 0.0000482 AC XY: 35 AN XY: 725762

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111930

Other (OTH) AF: 0.0000663 AC: 4 AN: 60352

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

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

Alfa AF: 0.0000661 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0042	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.21	N
PhyloP100		2.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.27
Sift	Benign	0.14	T
Sift4G	Benign	0.32	T
Polyphen		0.92	P
Vest4		0.36
MVP		0.79
MPC		0.25
ClinPred		0.19	T
GERP RS		4.5
Varity_R		0.12
gMVP		0.39
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs374989083; hg19: chr14-75376357; COSMIC: COSV106506095; COSMIC: COSV106506095;