14-74907493-T-C

Position:

• chr14-74907493-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031464.5(RPS6KL1):​c.1481A>G​(p.His494Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPS6KL1 NM_031464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26

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]

RPS6KL1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KL1	NM_031464.5	c.1481A>G	p.His494Arg	missense_variant	11/12	ENST00000557413.6	NP_113652.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KL1	ENST00000557413.6	c.1481A>G	p.His494Arg	missense_variant	11/12	5	NM_031464.5	ENSP00000450567.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.1481A>G (p.H494R) alteration is located in exon 10 (coding exon 9) of the RPS6KL1 gene. This alteration results from a A to G substitution at nucleotide position 1481, causing the histidine (H) at amino acid position 494 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;T;.;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;.;T;T;.
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.54	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	L;L;.;.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.7	.;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0050	.;D;D;T;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		0.98	D;D;.;.;D
Vest4		0.73
MutPred		0.40		Loss of glycosylation at S489 (P = 0.1099);Loss of glycosylation at S489 (P = 0.1099);.;.;Loss of glycosylation at S489 (P = 0.1099);
MVP		0.37
MPC		0.72
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-75374196;