NM_001018.5:c.140G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_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 allele was found at a frequency of 0.0000797 in 150,568 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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 criteria provided, multiple submitters, no conflicts B:4
• 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]

ACMG classification

Our verdict: Benign. The variant received -12 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 Benign. ClinVar VariationId is 440242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018.5. You can select a different transcript below to see updated ACMG 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	NP_001009.1
	RPS15	NM_001308226.2		c.161G>C	p.Arg54Pro	missense	Exon 3 of 4	NP_001295155.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPS15	ENST00000592588.7	TSL:1 MANE Select	c.140G>C	p.Arg47Pro	missense	Exon 3 of 4	ENSP00000467466.3
	RPS15	ENST00000592623.5	TSL:1	c.59G>C	p.Arg20Pro	missense	Exon 2 of 3	ENSP00000474433.2
	RPS15	ENST00000593052.5	TSL:2	c.161G>C	p.Arg54Pro	missense	Exon 3 of 4	ENSP00000466010.1

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

GnomAD2 exomes AF: 0.0249 AC: 3087 AN: 123918 AF XY: 0.0234

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0523 AC: 1239 AN: 23690

American (AMR) AF: 0.0551 AC: 1346 AN: 24418

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 867 AN: 19106

East Asian (EAS) AF: 0.0386 AC: 1335 AN: 34552

South Asian (SAS) AF: 0.0461 AC: 2816 AN: 61098

European-Finnish (FIN) AF: 0.0604 AC: 2442 AN: 40402

Middle Eastern (MID) AF: 0.0626 AC: 214 AN: 3420

European-Non Finnish (NFE) AF: 0.130 AC: 85606 AN: 656898

Other (OTH) AF: 0.0811 AC: 3376 AN: 41602

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000729 AC: 3 AN: 41136

American (AMR) AF: 0.000133 AC: 2 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.000288 AC: 3 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000594 AC: 4 AN: 67336

Other (OTH) AF: 0.00 AC: 0 AN: 2060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0240 Hom.: 0

ExAC AF: 0.0363 AC: 3887

ClinVar

ClinVar submissions as Germline

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

Source: dbNSFP v4.9

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
Eigen	Benign	-0.080
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.0024	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		9.3
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.26
Sift4G	Benign	0.081	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
Mutation Taster		=9/91	disease causing

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

Other links and lift over

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