NM_003161.4:c.76G>A

Variant names:

• chr17-59893260-G-A
• NM_003161.4:c.76G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003161.4(RPS6KB1):​c.76G>A​(p.Gly26Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6KB1 NM_003161.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.837

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.76G>A	p.Gly26Arg	missense	Exon 1 of 15	NP_003152.1	P23443-1
	RPS6KB1	NM_001272042.2		c.76G>A	p.Gly26Arg	missense	Exon 1 of 14	NP_001258971.1	P23443-5
	RPS6KB1	NM_001272060.2		c.7G>A	p.Gly3Arg	missense	Exon 1 of 15	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.76G>A	p.Gly26Arg	missense	Exon 1 of 15	ENSP00000225577.4	P23443-1
	RPS6KB1	ENST00000406116.7	TSL:1	c.76G>A	p.Gly26Arg	missense	Exon 1 of 15	ENSP00000384335.3	P23443-4
	RPS6KB1	ENST00000880476.1		c.76G>A	p.Gly26Arg	missense	Exon 1 of 15	ENSP00000550535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.55	N
PhyloP100		8.5
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.032	D
Polyphen		0.97	D
Vest4		0.84
MutPred		0.41		Loss of catalytic residue at V27 (P = 0.0423)
MVP		0.65
MPC		0.85
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.83
gMVP		0.52

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

hg19: chr17-57970621;