19-1440069-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001018.5(RPS15):c.140G>C(p.Arg47Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000797 in 150,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002413988).
• BP6: Variant 19-1440069-G-C is Benign according to our data. Variant chr19-1440069-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 440242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1440069-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPS15	NM_001018.5	c.140G>C	p.Arg47Pro	missense_variant	3/4	ENST00000592588.7
RPS15	NM_001308226.2	c.161G>C	p.Arg54Pro	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPS15	ENST00000592588.7	c.140G>C	p.Arg47Pro	missense_variant	3/4	1	NM_001018.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000797 AC: 12 AN: 150568 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000288

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0249 AC: 3087 AN: 123918 Hom.: 0 AF XY: 0.0234 AC XY: 1552 AN XY: 66208

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00590

Gnomad EAS exome AF: 0.0204

Gnomad SAS exome AF: 0.00657

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.110 AC: 99241 AN: 905186 Hom.: 1 Cov.: 37 AF XY: 0.107 AC XY: 48472 AN XY: 454910

Gnomad4 AFR exome AF: 0.0523

Gnomad4 AMR exome AF: 0.0551

Gnomad4 ASJ exome AF: 0.0454

Gnomad4 EAS exome AF: 0.0386

Gnomad4 SAS exome AF: 0.0461

Gnomad4 FIN exome AF: 0.0604

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.0811

GnomAD4 genome AF: 0.0000797 AC: 12 AN: 150568 Hom.: 0 Cov.: 32 AF XY: 0.0000544 AC XY: 4 AN XY: 73462

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000288

Gnomad4 NFE AF: 0.0000594

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0240 Hom.: 0

ExAC AF: 0.0363 AC: 3887

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 08, 2016

- -

RPS15-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;.;T;.;T;.;.;.;T;T;.
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0024	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.26
Sift4G	Benign	0.081	T;T;T;.;T;T;T;T;T;T;T
Polyphen		0.022	.;.;B;.;.;.;.;.;.;.;.
Vest4		0.80
MPC		1.9
ClinPred		0.093	T
GERP RS		3.2
Varity_R		0.97
gMVP		0.99

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: rs201657403; hg19: chr19-1440068; COSMIC: COSV51830899; COSMIC: COSV51830899;