17-59914627-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003161.4(RPS6KB1):c.313-8T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00915 in 1,610,504 control chromosomes in the GnomAD database, including 79 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0073 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (76 hom.)
• Consequence: RPS6KB1 NM_003161.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3328
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.28

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 17-59914627-T-A is Benign according to our data. Variant chr17-59914627-T-A is described in ClinVar as [Benign]. Clinvar id is 778132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 1110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS6KB1	NM_003161.4	c.313-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000225577.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS6KB1	ENST00000225577.9	c.313-8T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003161.4	A1

Frequencies

GnomAD3 genomes AF: 0.00729 AC: 1110 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00725 AC: 1812 AN: 250094 Hom.: 14 AF XY: 0.00764 AC XY: 1032 AN XY: 135144

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.00829

Gnomad ASJ exome AF: 0.00686

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00302

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.0129

GnomAD4 exome AF: 0.00934 AC: 13625 AN: 1458214 Hom.: 76 Cov.: 29 AF XY: 0.00912 AC XY: 6616 AN XY: 725534

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00846

Gnomad4 ASJ exome AF: 0.00640

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00327

Gnomad4 FIN exome AF: 0.00178

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.00834

GnomAD4 genome AF: 0.00730 AC: 1111 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00692 AC XY: 515 AN XY: 74466

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00830 Hom.: 4

Bravo AF: 0.00790

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0128

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	13
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.33
dbscSNV1_RF	Benign	0.32
SpliceAI score (max)		0.010		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: rs74702949; hg19: chr17-57991988;