chr3-23917766-T-C

Variant names:

• chr3-23917766-T-C
• rs56222205
• ENST00000354811.5:c.-94T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2347 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001253380.2. 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.-10-84T>C		intron	N/A	NP_002939.2
	RPL15	NM_001253380.2		c.-94T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_001240309.1	P61313-1
	RPL15	NM_001253380.2		c.-94T>C		5_prime_UTR	Exon 1 of 3	NP_001240309.1	P61313-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPL15	ENST00000354811.5	TSL:1	c.-94T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000346867.5	P61313-1
	RPL15	ENST00000354811.5	TSL:1	c.-94T>C		5_prime_UTR	Exon 1 of 3	ENSP00000346867.5	P61313-1
	RPL15	ENST00000307839.10	TSL:1 MANE Select	c.-10-84T>C		intron	N/A	ENSP00000309334.5	P61313-1

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

African (AFR) AF: 0.00297 AC: 80 AN: 26916

American (AMR) AF: 0.0107 AC: 294 AN: 27356

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 187 AN: 19096

East Asian (EAS) AF: 0.0000543 AC: 2 AN: 36838

South Asian (SAS) AF: 0.0292 AC: 1933 AN: 66296

European-Finnish (FIN) AF: 0.0276 AC: 1365 AN: 49512

Middle Eastern (MID) AF: 0.0285 AC: 98 AN: 3438

European-Non Finnish (NFE) AF: 0.0208 AC: 19673 AN: 946634

Other (OTH) AF: 0.0188 AC: 969 AN: 51490

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

African (AFR) AF: 0.00341 AC: 142 AN: 41588

American (AMR) AF: 0.0133 AC: 203 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.0246 AC: 119 AN: 4832

European-Finnish (FIN) AF: 0.0266 AC: 283 AN: 10622

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0221 AC: 1504 AN: 68020

Other (OTH) AF: 0.0222 AC: 47 AN: 2114

Alfa AF: 0.0191 Hom.: 11

Bravo AF: 0.0128

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.56
DANN	Benign	0.63
PhyloP100		-0.77
PromoterAI		-0.0053	Neutral
Mutation Taster		=293/7	polymorphism

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

Other links and lift over

dbSNP: rs56222205; hg19: chr3-23959257;