3-23917766-T-C

Position:

• chr3-23917766-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001253380.2(RPL15):​c.-94T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,379,922 control chromosomes in the GnomAD database, including 358 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (29 hom., cov: 33)
  • Exomes 𝑓: 0.020 (329 hom.)
• Consequence: RPL15 NM_001253380.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.774

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 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-23917766-T-C is Benign according to our data. Variant chr3-23917766-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1199763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0154 (2347/152346) while in subpopulation SAS AF= 0.0246 (119/4832). AF 95% confidence interval is 0.0212. There are 29 homozygotes in gnomad4. There are 1208 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2347 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL15	NM_002948.5	c.-10-84T>C		intron_variant		ENST00000307839.10	NP_002939.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL15	ENST00000307839.10	c.-10-84T>C		intron_variant		1	NM_002948.5	ENSP00000309334.5

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2347 AN: 152228 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.00342

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0246

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0200 AC: 24601 AN: 1227576 Hom.: 329 Cov.: 16 AF XY: 0.0203 AC XY: 12356 AN XY: 607572

Gnomad4 AFR exome AF: 0.00297

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.00979

Gnomad4 EAS exome AF: 0.0000543

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.0276

Gnomad4 NFE exome AF: 0.0208

Gnomad4 OTH exome AF: 0.0188

GnomAD4 genome AF: 0.0154 AC: 2347 AN: 152346 Hom.: 29 Cov.: 33 AF XY: 0.0162 AC XY: 1208 AN XY: 74502

Gnomad4 AFR AF: 0.00341

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0246

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0184 Hom.: 8

Bravo AF: 0.0128

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.56
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs56222205; hg19: chr3-23959257;