3-23917962-G-A

Position:

• chr3-23917962-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002948.5(RPL15):​c.103G>A​(p.Ala35Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,461,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: RPL15 NM_002948.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.31

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27570784).
• BS2: High AC in GnomAdExome4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPL15	NM_002948.5	c.103G>A	p.Ala35Thr	missense_variant	2/4	ENST00000307839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL15	ENST00000307839.10	c.103G>A	p.Ala35Thr	missense_variant	2/4	1	NM_002948.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249400 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135402

Gnomad AFR exome AF: 0.00

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

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: 0.0000351

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000434 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 06, 2023	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. ClinVar contains an entry for this variant (Variation ID: 1306432). This variant has not been reported in the literature in individuals affected with RPL15-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 35 of the RPL15 protein (p.Ala35Thr). This variant is present in population databases (no rsID available, gnomAD 0.002%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;T;T;T;.;.;.;T;T;.;T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	.;D;D;D;.;.;D;D;D;.;.;D;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.33	N;.;N;.;N;N;.;N;.;N;N;.;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N;.;N;N;N;.;.;N
REVEL	Uncertain	0.29
Sift	Benign	0.12	T;T;.;T;T;T;.;T;T;T;.;.;T
Sift4G	Benign	0.23	T;T;T;T;T;T;.;T;T;T;.;.;T
Polyphen		0.0	B;.;B;.;B;B;.;.;.;B;B;.;B
Vest4		0.34
MutPred		0.40		Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);Gain of phosphorylation at A35 (P = 0.0336);
MVP		0.50
MPC		1.5
ClinPred		0.34	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs1199176508; hg19: chr3-23959453;