chr19-1440069-G-A

Variant names:

• chr19-1440069-G-A
• rs201657403
• NM_001018.5:c.140G>A
• RPS15 p.Arg47Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Supporting

The NM_001018.5(RPS15):c.140G>A (p.Arg47Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The gene RPS15 is a cancer driver gene (CancerMine: 2 driver citations). The variant allele was found at a cumulative frequency of 0.0000161 (AC=23) in the gnomAD database across 1,425,242 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000661. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.32). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R47P: Benign (ClinVar VariationId 440242, 2 stars)

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: RPS15 NM_001018.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32
• Publications: 15 publications found

Genes affected

RPS15 (HGNC:10388): (ribosomal protein S15) 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 ribosomal protein that is a component of the 40S subunit. The protein belongs to the S19P family of ribosomal proteins. It is located in the cytoplasm. This gene has been found to be activated in various tumors, such as insulinomas, esophageal cancers, and colon cancers. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

RPS15 Gene-Disease associations (from GenCC):

• Diamond-Blackfan anemia

  Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 1 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000066 — very rare (O3 supporting [+1])

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001018.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RPS15 NM_001018.5	MANE Select	c.140G>A p.Arg47Gln	missense	Exon 3 of 4	Prot: NP_001009.1 UniProt:
	RPS15 NM_001308226.2		c.161G>A p.Arg54Gln	missense	Exon 3 of 4	Prot: NP_001295155.1 UniProt:

RPS15 NM_001018.5

MANE Select

HGVSc / HGVSpc.140G>Ap.Arg47Gln

Exon rankExon 3 of 4

missense

Prot: NP_001009.1UniProt: P62841

RPS15 NM_001308226.2

HGVSc / HGVSpc.161G>Ap.Arg54Gln

Exon rankExon 3 of 4

missense

Prot: NP_001295155.1UniProt: K7ELC2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RPS15 ENST00000592588.7	TSL:1MANE Select	c.140G>A p.Arg47Gln	missense	Exon 3 of 4	Prot: ENSP00000467466.3 UniProt:
	RPS15 ENST00000592623.5	TSL:1	c.59G>A p.Arg20Gln	missense	Exon 2 of 3	Prot: ENSP00000474433.2 UniProt:
	RPS15 ENST00000593052.5	TSL:2	c.161G>A p.Arg54Gln	missense	Exon 3 of 4	Prot: ENSP00000466010.1 UniProt:

RPS15 ENST00000592588.7

TSL:1MANE Select

HGVSc / HGVSpc.140G>Ap.Arg47Gln

Exon rankExon 3 of 4

missense

Prot: ENSP00000467466.3UniProt: P62841

RPS15 ENST00000592623.5

TSL:1

HGVSc / HGVSpc.59G>Ap.Arg20Gln

Exon rankExon 2 of 3

missense

Prot: ENSP00000474433.2UniProt: A0A0B4J2B4

RPS15 ENST00000593052.5

TSL:2

HGVSc / HGVSpc.161G>Ap.Arg54Gln

Exon rankExon 3 of 4

missense

Prot: ENSP00000466010.1UniProt: K7ELC2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000133	AC:2	Hom:0	AN:150832	Cov:32
GnomAD2 exomes	AF: 0.0000161	AC:2	Hom:	AN:123918	Cov:
GnomAD4 exome	AF: 0.0000165	AC:21	Hom:0	AN:1274410	Cov:37
GnomAD4 genome	AF: 0.0000133	AC:2	Hom:0	AN:150832	Cov:32
TOPMed (Bravo)	AF: 0.0000113	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:24714	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28394	0.00	0	28828
SCHEMA(Schizophrenia)	0.00	0	62282	0.00000835	1	119822

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.035
Eigen_PC	Benign	-0.027
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.63
GPN-Star LLR	N/A	-8.3
GPN-Star score	N/A	8.3
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.20	T
Mutation Taster	N/A	24/76	disease causing
MutationAssessor	Pathogenic	3.9	H
PhyloP100	Pathogenic	9.3
popEVE	Benign	-2.9
PrimateAI	Pathogenic	0.84	D
REVEL	Uncertain	0.32
Sift4G	Uncertain	0.041	D
Varity_R	N/A	0.88
VESM-3B	Benign	-8.3

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs201657403;

hg19: chr19-1440068;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar