chr17-59946914-A-G

Variant names:

• chr17-59946914-A-G
• rs180515
• NM_003161.4:c.*126A>G

Variant summary

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

The NM_003161.4(RPS6KB1):​c.*126A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 1,509,254 control chromosomes in the GnomAD database, including 95,242 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 0.33 (8588 hom., cov: 31)
  • Exomes 𝑓: 0.36 (86654 hom.)
• Consequence: RPS6KB1 NM_003161.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97
• Publications: 61 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

ENSG00000267318 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB1	NM_003161.4	MANE Select	c.*126A>G		3_prime_UTR	Exon 15 of 15	NP_003152.1
	RPS6KB1	NR_161455.1		n.1620A>G		non_coding_transcript_exon	Exon 14 of 14
	RPS6KB1	NR_161456.1		n.1771A>G		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6KB1	ENST00000225577.9	TSL:1 MANE Select	c.*126A>G		3_prime_UTR	Exon 15 of 15	ENSP00000225577.4
	RPS6KB1	ENST00000406116.7	TSL:1	c.1341-673A>G		intron	N/A	ENSP00000384335.3
	ENSG00000267318	ENST00000591035.1	TSL:3	c.149+1396A>G		intron	N/A	ENSP00000468280.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50451 AN: 151830 Hom.: 8576 Cov.: 31

Gnomad AFR AF: 0.278

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.341

GnomAD4 exome AF: 0.355 AC: 482096 AN: 1357306 Hom.: 86654 Cov.: 31 AF XY: 0.356 AC XY: 236837 AN XY: 665100

African (AFR) AF: 0.277 AC: 8322 AN: 30080

American (AMR) AF: 0.305 AC: 9020 AN: 29570

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 6249 AN: 20274

East Asian (EAS) AF: 0.459 AC: 17706 AN: 38564

South Asian (SAS) AF: 0.384 AC: 26583 AN: 69228

European-Finnish (FIN) AF: 0.333 AC: 15451 AN: 46462

Middle Eastern (MID) AF: 0.291 AC: 1531 AN: 5268

European-Non Finnish (NFE) AF: 0.356 AC: 377909 AN: 1061876

Other (OTH) AF: 0.345 AC: 19325 AN: 55984

GnomAD4 genome AF: 0.332 AC: 50499 AN: 151948 Hom.: 8588 Cov.: 31 AF XY: 0.332 AC XY: 24677 AN XY: 74256

African (AFR) AF: 0.278 AC: 11517 AN: 41444

American (AMR) AF: 0.329 AC: 5014 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3470

East Asian (EAS) AF: 0.443 AC: 2287 AN: 5164

South Asian (SAS) AF: 0.370 AC: 1785 AN: 4824

European-Finnish (FIN) AF: 0.332 AC: 3488 AN: 10520

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24145 AN: 67966

Other (OTH) AF: 0.348 AC: 733 AN: 2104

Alfa AF: 0.346 Hom.: 40934

Bravo AF: 0.327

Asia WGS AF: 0.441 AC: 1535 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.5
DANN	Benign	0.64
PhyloP100		3.0
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: rs180515; hg19: chr17-58024275;