chr3-23918027-G-C

Variant names:

• chr3-23918027-G-C
• rs2125251388
• NM_002948.5:c.168G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002948.5(RPL15):​c.168G>C​(p.Lys56Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K56E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RPL15 NM_002948.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002948.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL15	NM_002948.5	MANE Select	c.168G>C	p.Lys56Asn	missense	Exon 2 of 4	NP_002939.2
	RPL15	NM_001253379.2		c.168G>C	p.Lys56Asn	missense	Exon 2 of 4	NP_001240308.1	P61313-1
	RPL15	NM_001253380.2		c.168G>C	p.Lys56Asn	missense	Exon 1 of 3	NP_001240309.1	P61313-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL15	ENST00000307839.10	TSL:1 MANE Select	c.168G>C	p.Lys56Asn	missense	Exon 2 of 4	ENSP00000309334.5	P61313-1
	RPL15	ENST00000354811.5	TSL:1	c.168G>C	p.Lys56Asn	missense	Exon 1 of 3	ENSP00000346867.5	P61313-1
	RPL15	ENST00000456530.7	TSL:1	c.168G>C	p.Lys56Asn	missense	Exon 2 of 5	ENSP00000398788.2	P61313-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456522 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724708

African (AFR) AF: 0.00 AC: 0 AN: 33106

American (AMR) AF: 0.00 AC: 0 AN: 42714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110338

Other (OTH) AF: 0.00 AC: 0 AN: 60168

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		2.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.90	P
Vest4		0.81
MutPred		0.74		Loss of methylation at K56 (P = 0.0264)
MVP		0.74
MPC		3.0
ClinPred		1.0	D
GERP RS		3.0
PromoterAI		0.0080	Neutral
Varity_R		0.84
gMVP		0.99
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2125251388; hg19: chr3-23959518;