3-23917934-C-G

Position:

• chr3-23917934-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002948.5(RPL15):​c.75C>G​(p.Val25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00633 in 1,613,670 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (44 hom.)
• Consequence: RPL15 NM_002948.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.209

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 3-23917934-C-G is Benign according to our data. Variant chr3-23917934-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 436551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.209 with no splicing effect.
• BS2: High AC in GnomAd4 at 812 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL15	NM_002948.5	c.75C>G	p.Val25=	synonymous_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.75C>G	p.Val25=	synonymous_variant	2/4	1	NM_002948.5	ENSP00000309334	P1

Frequencies

GnomAD3 genomes AF: 0.00534 AC: 813 AN: 152218 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00818

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00732

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00529 AC: 1320 AN: 249536 Hom.: 7 AF XY: 0.00531 AC XY: 719 AN XY: 135424

Gnomad AFR exome AF: 0.000903

Gnomad AMR exome AF: 0.00330

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00206

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00728

Gnomad OTH exome AF: 0.00740

GnomAD4 exome AF: 0.00643 AC: 9397 AN: 1461334 Hom.: 44 Cov.: 31 AF XY: 0.00644 AC XY: 4681 AN XY: 726978

Gnomad4 AFR exome AF: 0.000867

Gnomad4 AMR exome AF: 0.00416

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.00702

Gnomad4 OTH exome AF: 0.00784

GnomAD4 genome AF: 0.00533 AC: 812 AN: 152336 Hom.: 3 Cov.: 33 AF XY: 0.00524 AC XY: 390 AN XY: 74490

Gnomad4 AFR AF: 0.00161

Gnomad4 AMR AF: 0.00817

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00732

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00529 Hom.: 2

Bravo AF: 0.00604

EpiCase AF: 0.00976

EpiControl AF: 0.00978

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	RPL15: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 02, 2018

- -

RPL15-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs35629664; hg19: chr3-23959425;