NM_001010.3:c.333G>T

Variant names:

• chr9-19378724-C-A
• rs1014493953
• NM_001010.3:c.333G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001010.3(RPS6):​c.333G>T​(p.Leu111Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPS6 NM_001010.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS6	NM_001010.3	c.333G>T	p.Leu111Phe	missense_variant	Exon 3 of 6	ENST00000380394.9	NP_001001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS6	ENST00000380394.9	c.333G>T	p.Leu111Phe	missense_variant	Exon 3 of 6	1	NM_001010.3	ENSP00000369757.4
RPS6	ENST00000380384.5	c.240G>T	p.Leu80Phe	missense_variant	Exon 2 of 5	1		ENSP00000369745.1
RPS6	ENST00000315377.4	c.240G>T	p.Leu80Phe	missense_variant	Exon 3 of 6	3		ENSP00000369743.1
RPS6	ENST00000380381.3	c.*625G>T		downstream_gene_variant		2		ENSP00000369741.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.333G>T (p.L111F) alteration is located in exon 3 (coding exon 3) of the RPS6 gene. This alteration results from a G to T substitution at nucleotide position 333, causing the leucine (L) at amino acid position 111 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;.;T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.074	D
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.91	P;P;P
Vest4		0.90
MutPred		0.72		Gain of methylation at K116 (P = 0.1022);.;.;
MVP		0.81
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs1014493953; hg19: chr9-19378722;