3-23917987-C-T

Position:

chr3-23917987-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12

Variant links:

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 links:

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]

NKIRAS1 links:

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ACMG classification

Classification made for transcript

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/exons	MANE	UniProt
RPL15	NM_002948.5 linkuse as main transcript	c.128C>T	p.Thr43Ile	missense_variant	2/4	ENST00000307839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL15	ENST00000307839.10 linkuse as main transcript	c.128C>T	p.Thr43Ile	missense_variant	2/4	1	NM_002948.5	P1	P61313-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248118

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134686

show subpopulations

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:

AN:

1459966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726392

show subpopulations

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 19, 2021

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). 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals affected with RPL15-related conditions. This variant is present in population databases (rs766954372, gnomAD 0.007%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

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

LIST_S2

Uncertain

0.96

.;D;D;D;.;.;D;D;D;.;.;D;.

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.5

M;.;M;.;M;M;.;M;.;M;M;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.84

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over