17-59926487-A-G

Variant names:

• chr17-59926487-A-G
• rs183590386
• NM_003161.4:c.434A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003161.4(RPS6KB1):​c.434A>G​(p.Asn145Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000763 in 1,611,888 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (2 hom.)
• Consequence: RPS6KB1 NM_003161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.89

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08428228).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KB1	NM_003161.4	c.434A>G	p.Asn145Ser	missense_variant	Exon 5 of 15	ENST00000225577.9	NP_003152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KB1	ENST00000225577.9	c.434A>G	p.Asn145Ser	missense_variant	Exon 5 of 15	1	NM_003161.4	ENSP00000225577.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 250920 AF XY: 0.0000885

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000788 AC: 115 AN: 1459544 Hom.: 2 Cov.: 29 AF XY: 0.0000771 AC XY: 56 AN XY: 726264

Gnomad4 AFR exome AF: 0.0000299 AC: 1 AN: 33428

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44696

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26108

Gnomad4 EAS exome AF: 0.00202 AC: 80 AN: 39624

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86192

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53410

Gnomad4 NFE exome AF: 9.01e-7 AC: 1 AN: 1110022

Gnomad4 Remaining exome AF: 0.000547 AC: 33 AN: 60310

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74502

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00154 AC: 0.00154261 AN: 0.00154261

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.000155

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.434A>G (p.N145S) alteration is located in exon 5 (coding exon 5) of the RPS6KB1 gene. This alteration results from a A to G substitution at nucleotide position 434, causing the asparagine (N) at amino acid position 145 to be replaced by a serine (S). 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	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;.;.;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.084	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.95	.;.;L;L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Benign	0.27
Sift	Benign	0.085	T;T;T;T
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.20	.;.;.;B
Vest4		0.67
MVP		0.68
MPC		1.3
ClinPred		0.25	T
GERP RS		5.5
Varity_R		0.47
gMVP		0.84
Mutation Taster		=63/37	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs183590386; hg19: chr17-58003848;