16-1945498-C-T

Position:

• chr16-1945498-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PVS1_Moderate PP3 BP6 BS2

The NM_005061.3(RPL3L):​c.1167+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,610,416 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (9 hom.)
• Consequence: RPL3L NM_005061.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.91

Genes affected

RPL3L (HGNC:10351): (ribosomal protein L3 like) This gene encodes a protein that shares sequence similarity with ribosomal protein L3. The protein belongs to the L3P family of ribosomal proteins. Unlike the ubiquitous expression of ribosomal protein genes, this gene has a tissue-specific pattern of expression, with the highest levels of expression in skeletal muscle and heart. It is not currently known whether the encoded protein is a functional ribosomal protein or whether it has evolved a function that is independent of the ribosome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.097222224 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP3: Multiple lines of computational evidence support a deleterious effect 6: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen, phyloP100way_vertebrate [when BayesDel_addAF, MutationTaster was below the threshold]
• BP6: Variant 16-1945498-C-T is Benign according to our data. Variant chr16-1945498-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2413034.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPL3L	NM_005061.3	c.1167+1G>A		splice_donor_variant, intron_variant		ENST00000268661.8	NP_005052.1
RPL3L	XM_011522571.3	c.1182+1G>A		splice_donor_variant, intron_variant			XP_011520873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPL3L	ENST00000268661.8	c.1167+1G>A		splice_donor_variant, intron_variant		1	NM_005061.3	ENSP00000268661.7

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00285

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00118 AC: 289 AN: 244244 Hom.: 1 AF XY: 0.00124 AC XY: 164 AN XY: 132566

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000819

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000472

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00257 AC: 3746 AN: 1458142 Hom.: 9 Cov.: 32 AF XY: 0.00244 AC XY: 1772 AN XY: 725042

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000877

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000474

Gnomad4 NFE exome AF: 0.00316

Gnomad4 OTH exome AF: 0.00261

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74450

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00285

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00161

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.000915 AC: 111

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	RPL3L: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2023	Identified by meta-analysis of GWAS data in association with atrial fibrillation; transcript analysis of c.1167+1G>A indicates that it results in skipping of exon 9 (Thorolfsdottir et al., 2018); Canonical splice site variant in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 32514796, Nannapaneni2022[article], 30271950, 36291431, 35323613, 34662886) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs140192228; hg19: chr16-1995499;