rs180535

Variant names:

• chr17-59919654-T-C
• rs180535
• NM_003161.4:c.381+4951T>C

Variant summary

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

The NM_003161.4(RPS6KB1):​c.381+4951T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 151,926 control chromosomes in the GnomAD database, including 1,680 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 0.14 (1680 hom., cov: 31)
• Consequence: RPS6KB1 NM_003161.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.672
• Publications: 13 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: MODERATE, LIMITED Submitted by: ClinGen, PanelApp Australia

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003161.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB1	NM_003161.4	MANE Select	c.381+4951T>C		intron	N/A	NP_003152.1	P23443-1
	RPS6KB1	NM_001272042.2		c.313-6781T>C		intron	N/A	NP_001258971.1	P23443-5
	RPS6KB1	NM_001272060.2		c.312+4951T>C		intron	N/A	NP_001258989.1	P23443-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB1	ENST00000225577.9	TSL:1 MANE Select	c.381+4951T>C		intron	N/A	ENSP00000225577.4	P23443-1
	RPS6KB1	ENST00000406116.7	TSL:1	c.381+4951T>C		intron	N/A	ENSP00000384335.3	P23443-4
	RPS6KB1	ENST00000880476.1		c.381+4951T>C		intron	N/A	ENSP00000550535.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21591 AN: 151808 Hom.: 1681 Cov.: 31

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.261

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.0535

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.153

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

GnomAD4 genome AF: 0.142 AC: 21584 AN: 151926 Hom.: 1680 Cov.: 31 AF XY: 0.142 AC XY: 10566 AN XY: 74258

African (AFR) AF: 0.105 AC: 4357 AN: 41450

American (AMR) AF: 0.162 AC: 2465 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 583 AN: 3468

East Asian (EAS) AF: 0.0534 AC: 276 AN: 5164

South Asian (SAS) AF: 0.106 AC: 511 AN: 4816

European-Finnish (FIN) AF: 0.157 AC: 1655 AN: 10544

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.164 AC: 11129 AN: 67942

Other (OTH) AF: 0.151 AC: 317 AN: 2102

Alfa AF: 0.159 Hom.: 3371

Bravo AF: 0.141

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.0
DANN	Benign	0.70
PhyloP100		0.67
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: rs180535; hg19: chr17-57997015;