rs180519

Variant names:

• chr17-59938910-G-A
• rs180519
• NM_003161.4:c.1120-1926G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003161.4(RPS6KB1):​c.1120-1926G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 151,994 control chromosomes in the GnomAD database, including 25,843 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25843 hom., cov: 31)
• Consequence: RPS6KB1 NM_003161.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801
• Publications: 9 publications found

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]

RPS6KB1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6KB1	NM_003161.4	c.1120-1926G>A		intron_variant	Intron 12 of 14	ENST00000225577.9	NP_003152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6KB1	ENST00000225577.9	c.1120-1926G>A		intron_variant	Intron 12 of 14	1	NM_003161.4	ENSP00000225577.4

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84868 AN: 151876 Hom.: 25791 Cov.: 31

Gnomad AFR AF: 0.818

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.554

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.559 AC: 84980 AN: 151994 Hom.: 25843 Cov.: 31 AF XY: 0.556 AC XY: 41270 AN XY: 74282

African (AFR) AF: 0.818 AC: 33926 AN: 41480

American (AMR) AF: 0.530 AC: 8083 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1447 AN: 3468

East Asian (EAS) AF: 0.561 AC: 2897 AN: 5164

South Asian (SAS) AF: 0.425 AC: 2049 AN: 4816

European-Finnish (FIN) AF: 0.429 AC: 4521 AN: 10550

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30261 AN: 67944

Other (OTH) AF: 0.559 AC: 1176 AN: 2104

Alfa AF: 0.484 Hom.: 23997

Bravo AF: 0.576

Asia WGS AF: 0.567 AC: 1973 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.81
DANN	Benign	0.38
PhyloP100		-0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.98
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs180519; hg19: chr17-58016271;