17-59946640-A-C

Position:

• chr17-59946640-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003161.4(RPS6KB1):​c.1430A>C​(p.Glu477Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KB1 NM_003161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.88

Genes affected

RPS6KB1 (HGNC:10436): (ribosomal protein S6 kinase B1) This gene encodes a member of the ribosomal S6 kinase family of serine/threonine kinases. The encoded protein responds to mTOR (mammalian target of rapamycin) signaling to promote protein synthesis, cell growth, and cell proliferation. Activity of this gene has been associated with human cancer. Alternatively spliced transcript variants have been observed. The use of alternative translation start sites results in isoforms with longer or shorter N-termini which may differ in their subcellular localizations. There are two pseudogenes for this gene on chromosome 17. [provided by RefSeq, Jan 2013]

ENSG00000267318 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RPS6KB1. . Gene score misZ 3.9009 (greater than the threshold 3.09). Trascript score misZ 3.431 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22813618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPS6KB1	NM_003161.4	c.1430A>C	p.Glu477Ala	missense_variant	15/15	ENST00000225577.9	NP_003152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPS6KB1	ENST00000225577.9	c.1430A>C	p.Glu477Ala	missense_variant	15/15	1	NM_003161.4	ENSP00000225577.4
ENSG00000267318	ENST00000591035.1	c.149+1122A>C		intron_variant		3		ENSP00000468280.1

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

Jan 06, 2023

The c.1430A>C (p.E477A) alteration is located in exon 15 (coding exon 15) of the RPS6KB1 gene. This alteration results from a A to C substitution at nucleotide position 1430, causing the glutamic acid (E) at amino acid position 477 to be replaced by an alanine (A). 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	0.14
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.5	.;.;L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.45	T;T;T
Polyphen		0.0050	.;.;B
Vest4		0.43
MutPred		0.12		.;.;Gain of glycosylation at T478 (P = 0.0755);
MVP		0.94
MPC		1.2
ClinPred		0.55	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.11
gMVP		0.45

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: chr17-58024001;