chr19-1440069-G-C

Variant names:

• chr19-1440069-G-C
• rs201657403
• NM_001018.5:c.140G>C
• RPS15 p.Arg47Pro

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). PM2_SupportingBP4BP6_Strong

The NM_001018.5(RPS15):c.140G>C (p.Arg47Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000229, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely benign. 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). Variant has been reported in ClinVar as Benign/Likely Benign (★★). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.11 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: RPS15 NM_001018.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 9.32
• Publications: 1 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000229 — borderline rare for AD/XL gene (threshold 0.0001) — PM2 supporting.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).

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>C p.Arg47Pro	missense	Exon 3 of 4	Prot: NP_001009.1 UniProt:
	RPS15 NM_001308226.2		c.161G>C p.Arg54Pro	missense	Exon 3 of 4	Prot: NP_001295155.1 UniProt:

RPS15 NM_001018.5

MANE Select

HGVSc / HGVSpc.140G>Cp.Arg47Pro

Exon rankExon 3 of 4

missense

Prot: NP_001009.1UniProt: P62841

RPS15 NM_001308226.2

HGVSc / HGVSpc.161G>Cp.Arg54Pro

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>C p.Arg47Pro	missense	Exon 3 of 4	Prot: ENSP00000467466.3 UniProt:
	RPS15 ENST00000592623.5	TSL:1	c.59G>C p.Arg20Pro	missense	Exon 2 of 3	Prot: ENSP00000474433.2 UniProt:
	RPS15 ENST00000593052.5	TSL:2	c.161G>C p.Arg54Pro	missense	Exon 3 of 4	Prot: ENSP00000466010.1 UniProt:

RPS15 ENST00000592588.7

TSL:1MANE Select

HGVSc / HGVSpc.140G>Cp.Arg47Pro

Exon rankExon 3 of 4

missense

Prot: ENSP00000467466.3UniProt: P62841

RPS15 ENST00000592623.5

TSL:1

HGVSc / HGVSpc.59G>Cp.Arg20Pro

Exon rankExon 2 of 3

missense

Prot: ENSP00000474433.2UniProt: A0A0B4J2B4

RPS15 ENST00000593052.5

TSL:2

HGVSc / HGVSpc.161G>Cp.Arg54Pro

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: 0.0000797	AC:12	Hom:0	AN:150568	Cov:32
GnomAD2 exomes	AF: 0.0249	AC:3087	Hom:	AN:123918	Cov:
GnomAD4 exome Warning	AF: 0.110	AC:99241	Hom:1	AN:905186	Cov:37
GnomAD4 genome Warning	AF: 0.0000797	AC:12	Hom:0	AN:150568	Cov:32
TOPMed (Bravo)	AF: 0.0000491	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0220	AC:544	Hom:0	AN:24714	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00212	AC:19	Hom:0	AN:8960	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	22556	0.0000344	1	29080

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	RPS15-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Benign	0.90
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.015
GPN-Star LLR	N/A	-9.1
GPN-Star score	N/A	9.1
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0024	T
MetaSVM	Uncertain	-0.21	T
Mutation Taster	N/A	9/91	disease causing
MutationAssessor	Pathogenic	3.8	H
PhyloP100	Pathogenic	9.3
popEVE	Benign	-2.8
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.26
Sift4G	Benign	0.081	T
Varity_R	N/A	0.97
VESM-3B	Benign	-11

Showing 25 of 25 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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;

COSMIC: COSV51830899;

COSMIC: COSV51830899;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar