chr3-23917944-C-A

Position:

• chr3-23917944-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002948.5(RPL15):​c.85C>A​(p.Gln29Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RPL15 NM_002948.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

Genes affected

RPL15 (HGNC:10306): (ribosomal protein L15) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of four RNA species and approximately 80 structurally distinct proteins. This gene encodes a member of the L15E family of ribosomal proteins and a component of the 60S subunit. This gene shares sequence similarity with the yeast ribosomal protein YL10 gene. Elevated expression of this gene has been observed in esophageal tumors and gastric cancer tissues, and deletion of this gene has been observed in a Diamond-Blackfan anemia (DBA) patient. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Mar 2017]

RPL15 (HGNC:):

NKIRAS1 (HGNC:17899): (NFKB inhibitor interacting Ras like 1) Predicted to enable GTPase activating protein binding activity. Predicted to be involved in I-kappaB kinase/NF-kappaB signaling. Predicted to act upstream of or within several processes, including Ral protein signal transduction; lung alveolus development; and surfactant homeostasis. Located in cytosol and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL15	NM_002948.5	c.85C>A	p.Gln29Lys	missense_variant	2/4	ENST00000307839.10	NP_002939.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL15	ENST00000307839.10	c.85C>A	p.Gln29Lys	missense_variant	2/4	1	NM_002948.5	ENSP00000309334.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000614 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2022

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 29 of the RPL15 protein (p.Gln29Lys). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with RPL15-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;T;T;T;T;T;.;.;.;T;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	.;D;D;D;.;.;D;D;D;.;.;D;.
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.4	M;.;M;.;M;M;.;M;.;M;M;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;N;.;N;N;N;.;N;N;N;.;.;N
REVEL	Uncertain	0.54
Sift	Benign	0.038	D;D;.;D;D;D;.;D;D;D;.;.;D
Sift4G	Benign	0.19	T;T;T;T;T;T;.;T;T;T;.;.;T
Polyphen		0.0	B;.;B;.;B;B;.;.;.;B;B;.;B
Vest4		0.80
MutPred		0.56		Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);Gain of methylation at Q29 (P = 0.0139);
MVP		0.80
MPC		1.8
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.45
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-23959435;