14-74909741-C-T

Variant names:

• chr14-74909741-C-T
• rs1465450200
• NM_031464.5:c.1072G>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.1072G>A​(p.Gly358Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G358R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPS6KL1 NM_031464.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.406
• 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=0.10750267).

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.1072G>A	p.Gly358Ser	missense	Exon 8 of 12	NP_113652.2	Q9Y6S9-1
	RPS6KL1	NM_001370252.1		c.1072G>A	p.Gly358Ser	missense	Exon 7 of 11	NP_001357181.1
	RPS6KL1	NM_001370253.1		c.1027G>A	p.Gly343Ser	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.1072G>A	p.Gly358Ser	missense	Exon 8 of 12	ENSP00000450567.1	Q9Y6S9-1
	RPS6KL1	ENST00000555009.5	TSL:1	n.979G>A		non_coding_transcript_exon	Exon 6 of 12	ENSP00000450660.1	Q9Y6S9-2
	RPS6KL1	ENST00000961459.1		c.1120G>A	p.Gly374Ser	missense	Exon 9 of 13	ENSP00000631518.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455450 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724262

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47916

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111400

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.41
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.057
Sift	Benign	0.034	D
Sift4G	Benign	0.090	T
Polyphen		0.038	B
Vest4		0.15
MutPred		0.55		Loss of catalytic residue at P354 (P = 0.074)
MVP		0.53
MPC		0.18
ClinPred		0.13	T
GERP RS		3.3
Varity_R		0.076
gMVP		0.39
Mutation Taster		=99/1	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: rs1465450200; hg19: chr14-75376444;