chr14-90894517-T-G

Position:

• chr14-90894517-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004755.4(RPS6KA5):​c.1540A>C​(p.Lys514Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KA5 NM_004755.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

Genes affected

RPS6KA5 (HGNC:10434): (ribosomal protein S6 kinase A5) Enables ATP binding activity and protein serine/threonine kinase activity. Involved in several processes, including histone-serine phosphorylation; positive regulation of histone modification; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08561811).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KA5	NM_004755.4	c.1540A>C	p.Lys514Gln	missense_variant	13/17	ENST00000614987.5	NP_004746.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KA5	ENST00000614987.5	c.1540A>C	p.Lys514Gln	missense_variant	13/17	1	NM_004755.4	ENSP00000479667	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Dec 28, 2022

The c.1540A>C (p.K514Q) alteration is located in exon 13 (coding exon 13) of the RPS6KA5 gene. This alteration results from a A to C substitution at nucleotide position 1540, causing the lysine (K) at amino acid position 514 to be replaced by a glutamine (Q). 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	Benign	0.077
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.086	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.93	L;.;L
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	.;N;N
REVEL	Benign	0.066
Sift	Benign	0.26	.;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.0030	B;.;B
Vest4		0.21
MutPred		0.50		Loss of methylation at K514 (P = 0.0121);.;Loss of methylation at K514 (P = 0.0121);
MVP		0.51
ClinPred		0.37	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.43

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: chr14-91360861;