17-59946963-A-G

Variant names:

• chr17-59946963-A-G
• rs1051424
• NM_003161.4:c.*175A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000225577.9(RPS6KB1):​c.*175A>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 0.194 in 1,437,914 control chromosomes in the GnomAD database, including 30,046 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 0.15 (2287 hom., cov: 31)
  • Exomes 𝑓: 0.20 (27759 hom.)
• Consequence: RPS6KB1 ENST00000225577.9 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.290
• Publications: 36 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000225577.9. 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.*175A>G		3_prime_UTR	Exon 15 of 15	NP_003152.1
	RPS6KB1	NR_161455.1		n.1669A>G		non_coding_transcript_exon	Exon 14 of 14
	RPS6KB1	NR_161456.1		n.1820A>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.*175A>G		3_prime_UTR	Exon 15 of 15	ENSP00000225577.4
	RPS6KB1	ENST00000406116.7	TSL:1	c.1341-624A>G		intron	N/A	ENSP00000384335.3
	ENSG00000267318	ENST00000591035.1	TSL:3	c.149+1445A>G		intron	N/A	ENSP00000468280.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22957 AN: 151968 Hom.: 2279 Cov.: 31

Gnomad AFR AF: 0.0377

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.391

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.152

GnomAD4 exome AF: 0.199 AC: 255325 AN: 1285828 Hom.: 27759 Cov.: 31 AF XY: 0.201 AC XY: 125602 AN XY: 624280

African (AFR) AF: 0.0268 AC: 757 AN: 28238

American (AMR) AF: 0.135 AC: 2861 AN: 21156

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 2682 AN: 18800

East Asian (EAS) AF: 0.423 AC: 14729 AN: 34854

South Asian (SAS) AF: 0.270 AC: 16768 AN: 62120

European-Finnish (FIN) AF: 0.178 AC: 5849 AN: 32942

Middle Eastern (MID) AF: 0.105 AC: 473 AN: 4496

European-Non Finnish (NFE) AF: 0.195 AC: 201225 AN: 1029832

Other (OTH) AF: 0.187 AC: 9981 AN: 53390

GnomAD4 genome AF: 0.151 AC: 22973 AN: 152086 Hom.: 2287 Cov.: 31 AF XY: 0.153 AC XY: 11353 AN XY: 74324

African (AFR) AF: 0.0376 AC: 1562 AN: 41526

American (AMR) AF: 0.151 AC: 2311 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3470

East Asian (EAS) AF: 0.390 AC: 2022 AN: 5182

South Asian (SAS) AF: 0.263 AC: 1265 AN: 4816

European-Finnish (FIN) AF: 0.175 AC: 1843 AN: 10550

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.191 AC: 12996 AN: 67956

Other (OTH) AF: 0.162 AC: 342 AN: 2114

Alfa AF: 0.175 Hom.: 7197

Bravo AF: 0.141

Asia WGS AF: 0.351 AC: 1220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		0.29
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: rs1051424; hg19: chr17-58024324;