NM_002948.5:c.128C>T

Variant names:

• chr3-23917987-C-T
• rs766954372
• NM_002948.5:c.128C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002948.5(RPL15):​c.128C>T​(p.Thr43Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RPL15 NM_002948.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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]

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPL15	NM_002948.5	c.128C>T	p.Thr43Ile	missense_variant	Exon 2 of 4	ENST00000307839.10	NP_002939.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL15	ENST00000307839.10	c.128C>T	p.Thr43Ile	missense_variant	Exon 2 of 4	1	NM_002948.5	ENSP00000309334.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248118 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134686

Gnomad AFR exome AF: 0.0000638

Gnomad AMR exome AF: 0.00

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: 6.85e-7 AC: 1 AN: 1459966 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726392

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 43 of the RPL15 protein (p.Thr43Ile). This variant is present in population databases (rs766954372, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RPL15-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;T;D;T;D;D;.;.;.;D;D;.;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	.;D;D;D;.;.;D;D;D;.;.;D;.
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.5	M;.;M;.;M;M;.;M;.;M;M;.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D;D;.;D;D;D;.;D;D;D;.;.;D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;.;D;D;D;.;D;D;D;.;.;D
Sift4G	Uncertain	0.027	D;D;D;D;D;D;.;D;D;D;.;.;D
Polyphen		0.074	B;.;B;.;B;B;.;.;.;B;B;.;B
Vest4		0.68
MutPred		0.58		Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);Loss of phosphorylation at T43 (P = 0.0016);
MVP		0.68
MPC		1.9
ClinPred		0.62	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs766954372; hg19: chr3-23959478;