Variant chr16-1945498-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PVS1_ModeratePP3BS2

The NM_005061.3(RPL3L):c.1167+1G>A variant causes a splice donor 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0026 ( 9 hom. )

Consequence

RPL3L
NM_005061.3 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91

Variant links:

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]

RPL3L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.048611112 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]

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPL3L	NM_005061.3 linkuse as main transcript	c.1167+1G>A		splice_donor_variant		ENST00000268661.8
RPL3L	XM_011522571.3 linkuse as main transcript	c.1182+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPL3L	ENST00000268661.8 linkuse as main transcript	c.1167+1G>A		splice_donor_variant		1	NM_005061.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152156

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00124

AC XY:

164

AN XY:

132566

show subpopulations

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.:

Cov.:

AF XY:

0.00244

AC XY:

1772

AN XY:

725042

show subpopulations

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.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74450

show subpopulations

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.:

Bravo

AF:

0.00161

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.000915

AC:

111

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

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

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over