14-74907022-C-A

Variant names:

• chr14-74907022-C-A
• rs577376442
• NM_031464.5:c.1642G>T

Variant summary

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

The NM_031464.5(RPS6KL1):​c.1642G>T​(p.Val548Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 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: 6.9e-7 (0 hom.)
• Consequence: RPS6KL1 NM_031464.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.733
• 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: 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=0.060735673).

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.1642G>T	p.Val548Leu	missense	Exon 12 of 12	NP_113652.2	Q9Y6S9-1
	RPS6KL1	NM_001370255.1		c.940G>T	p.Val314Leu	missense	Exon 10 of 11	NP_001357184.1
	RPS6KL1	NM_001370256.1		c.946G>T	p.Val316Leu	missense	Exon 9 of 9	NP_001357185.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KL1	ENST00000557413.6	TSL:5 MANE Select	c.1642G>T	p.Val548Leu	missense	Exon 12 of 12	ENSP00000450567.1	Q9Y6S9-1
	RPS6KL1	ENST00000555910.5	TSL:1	c.124G>T	p.Val42Leu	missense	Exon 2 of 3	ENSP00000451986.1	H0YJR0
	RPS6KL1	ENST00000555009.5	TSL:1	n.1549G>T		non_coding_transcript_exon	Exon 10 of 12	ENSP00000450660.1	Q9Y6S9-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457930 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725184

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25832

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109814

Other (OTH) AF: 0.00 AC: 0 AN: 60232

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.74
DEOGEN2	Benign	0.00082	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.73
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.021
Sift	Benign	0.034	D
Sift4G	Benign	0.20	T
Polyphen		0.22	B
Vest4		0.023
MutPred		0.31		Loss of MoRF binding (P = 0.0856)
MVP		0.58
MPC		0.18
ClinPred		0.21	T
GERP RS		3.2
PromoterAI		0.015	Neutral
Varity_R		0.050
gMVP		0.19
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs577376442; hg19: chr14-75373725;