19-1440051-A-C

Variant names:

• chr19-1440051-A-C
• rs752461630
• NM_001018.5:c.122A>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001018.5(RPS15):​c.122A>C​(p.Gln41Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000385 in 1,558,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: RPS15 NM_001018.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.75

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPS15	NM_001018.5	c.122A>C	p.Gln41Pro	missense_variant	Exon 3 of 4	ENST00000592588.7	NP_001009.1
RPS15	NM_001308226.2	c.143A>C	p.Gln48Pro	missense_variant	Exon 3 of 4		NP_001295155.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPS15	ENST00000592588.7	c.122A>C	p.Gln41Pro	missense_variant	Exon 3 of 4	1	NM_001018.5	ENSP00000467466.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000127 AC: 2 AN: 158074 Hom.: 0 AF XY: 0.0000118 AC XY: 1 AN XY: 84718

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000805

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000356 AC: 5 AN: 1406016 Hom.: 0 Cov.: 30 AF XY: 0.00000432 AC XY: 3 AN XY: 694116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000111

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: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74390

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122A>C (p.Q41P) alteration is located in exon 3 (coding exon 3) of the RPS15 gene. This alteration results from a A to C substitution at nucleotide position 122, causing the glutamine (Q) at amino acid position 41 to be replaced by a proline (P). 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	0.61
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
DANN	Benign	0.81
DEOGEN2	Benign	0.033	T;.;T;.;T;.;.;.;T;T;.
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.017
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	.;.;T;T;T;T;T;.;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	.;.;M;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
REVEL	Uncertain	0.35
Sift4G	Benign	0.19	T;T;T;.;T;T;T;T;T;T;T
Polyphen		0.0010	.;.;B;.;.;.;.;.;.;.;.
Vest4		0.90
MutPred		0.39		.;.;Gain of glycosylation at Q41 (P = 0.0052);.;.;.;Gain of glycosylation at Q41 (P = 0.0052);.;.;Gain of glycosylation at Q41 (P = 0.0052);.;
MVP		0.94
MPC		1.6
ClinPred		0.43	T
GERP RS		4.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		4.1
Varity_R		0.88
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs752461630; hg19: chr19-1440050;