rs79508780

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000333213.11(TSEN54):c.568G>A(p.Val190Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.053 in 1,614,038 control chromosomes in the GnomAD database, including 2,598 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V190L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.041 ( 180 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2418 hom. )

Consequence

TSEN54
ENST00000333213.11 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0780

Variant links:

Genes affected

TSEN54 (HGNC:27561): (tRNA splicing endonuclease subunit 54) This gene encodes a subunit of the tRNA splicing endonuclease complex, which catalyzes the removal of introns from precursor tRNAs. The complex is also implicated in pre-mRNA 3-prime end processing. Mutations in this gene result in pontocerebellar hypoplasia type 2.[provided by RefSeq, Oct 2009]

TSEN54 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002036363).

BP6

Variant 17-75521455-G-A is Benign according to our data. Variant chr17-75521455-G-A is described in ClinVar as [Benign]. Clinvar id is 137758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75521455-G-A is described in Lovd as [Likely_benign]. Variant chr17-75521455-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3 linkuse as main transcript	c.568G>A	p.Val190Met	missense_variant	7/11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11 linkuse as main transcript	c.568G>A	p.Val190Met	missense_variant	7/11	1	NM_207346.3	ENSP00000327487	P1	Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.0413

AC:

6281

AN:

152188

Hom.:

180

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0102

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0324

Gnomad ASJ

AF:

0.0712

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0474

Gnomad FIN

AF:

0.0801

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0572

Gnomad OTH

AF:

0.0363

GnomAD3 exomes

AF:

0.0471

AC:

11832

AN:

251258

Hom.:

380

AF XY:

0.0494

AC XY:

6708

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.00788

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0739

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0495

Gnomad FIN exome

AF:

0.0812

Gnomad NFE exome

AF:

0.0575

Gnomad OTH exome

AF:

0.0492

GnomAD4 exome

AF:

0.0543

AC:

79307

AN:

1461732

Hom.:

2418

Cov.:

AF XY:

0.0546

AC XY:

39691

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.00726

Gnomad4 AMR exome

AF:

0.0260

Gnomad4 ASJ exome

AF:

0.0741

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0504

Gnomad4 FIN exome

AF:

0.0863

Gnomad4 NFE exome

AF:

0.0573

Gnomad4 OTH exome

AF:

0.0506

GnomAD4 genome

AF:

0.0412

AC:

6276

AN:

152306

Hom.:

180

Cov.:

AF XY:

0.0419

AC XY:

3122

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0102

Gnomad4 AMR

AF:

0.0323

Gnomad4 ASJ

AF:

0.0712

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0468

Gnomad4 FIN

AF:

0.0801

Gnomad4 NFE

AF:

0.0572

Gnomad4 OTH

AF:

0.0360

Alfa

AF:

0.0517

Hom.:

152

Bravo

AF:

0.0360

TwinsUK

AF:

0.0609

AC:

226

ALSPAC

AF:

0.0568

AC:

219

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0574

AC:

494

ExAC

AF:

0.0479

AC:

5814

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0511

EpiControl

AF:

0.0489

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Pontoneocerebellar hypoplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.64

CADD

Benign

6.4

DANN

Benign

0.44

DEOGEN2

Benign

0.018

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.58

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.47

REVEL

Benign

0.085

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

0.95

Vest4

0.037

MPC

0.26

ClinPred

0.0063

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.023

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

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