9-19376387-T-C

Variant names:

• chr9-19376387-T-C
• rs3209388
• NM_001010.3:c.656A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001010.3(RPS6):​c.656A>G​(p.Glu219Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPS6 NM_001010.3 missense, splice_region
• Scores: Splicing: ADA: 0.7142
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.96
• Publications: 1 publications found

Genes affected

RPS6 (HGNC:10429): (ribosomal protein S6) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a cytoplasmic ribosomal protein that is a component of the 40S subunit. The protein belongs to the S6E family of ribosomal proteins. It is the major substrate of protein kinases in the ribosome, with subsets of five C-terminal serine residues phosphorylated by different protein kinases. Phosphorylation is induced by a wide range of stimuli, including growth factors, tumor-promoting agents, and mitogens. Dephosphorylation occurs at growth arrest. The protein may contribute to the control of cell growth and proliferation through the selective translation of particular classes of mRNA. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010.3. 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
	RPS6	NM_001010.3	MANE Select	c.656A>G	p.Glu219Gly	missense splice_region	Exon 6 of 6	NP_001001.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS6	ENST00000380394.9	TSL:1 MANE Select	c.656A>G	p.Glu219Gly	missense splice_region	Exon 6 of 6	ENSP00000369757.4
	RPS6	ENST00000380384.5	TSL:1	c.563A>G	p.Glu188Gly	missense splice_region	Exon 5 of 5	ENSP00000369745.1
	RPS6	ENST00000889073.1		c.680A>G	p.Glu227Gly	missense splice_region	Exon 6 of 6	ENSP00000559132.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.68
MutPred		0.22		Loss of methylation at K215 (P = 0.0686)
MVP		0.74
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.82
gMVP		0.61
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.71
dbscSNV1_RF	Pathogenic	0.77
SpliceAI score (max)		0.070		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: rs3209388; hg19: chr9-19376385;