rs8079373

Variant summary

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

The NM_207346.3(TSEN54):c.114T>G(p.His38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,586,916 control chromosomes in the GnomAD database, including 17,494 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 3419 hom., cov: 33)

Exomes 𝑓: 0.13 ( 14075 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.442

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=9.0411305E-4).

BP6

Variant 17-75516803-T-G is Benign according to our data. Variant chr17-75516803-T-G is described in ClinVar as [Benign]. Clinvar id is 96671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75516803-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN54	NM_207346.3 linkuse as main transcript	c.114T>G	p.His38Gln	missense_variant	2/11	ENST00000333213.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN54	ENST00000333213.11 linkuse as main transcript	c.114T>G	p.His38Gln	missense_variant	2/11	1	NM_207346.3	P1	Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.186

AC:

28208

AN:

152048

Hom.:

3407

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.134

Gnomad ASJ

AF:

0.163

Gnomad EAS

AF:

0.0204

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.191

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.179

GnomAD3 exomes

AF:

0.121

AC:

25375

AN:

210344

Hom.:

1902

AF XY:

0.120

AC XY:

14089

AN XY:

117864

show subpopulations

Gnomad AFR exome

AF:

0.317

Gnomad AMR exome

AF:

0.0819

Gnomad ASJ exome

AF:

0.155

Gnomad EAS exome

AF:

0.0162

Gnomad SAS exome

AF:

0.0941

Gnomad FIN exome

AF:

0.106

Gnomad NFE exome

AF:

0.136

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.134

AC:

191660

AN:

1434752

Hom.:

14075

Cov.:

AF XY:

0.132

AC XY:

94121

AN XY:

713076

show subpopulations

Gnomad4 AFR exome

AF:

0.349

Gnomad4 AMR exome

AF:

0.0866

Gnomad4 ASJ exome

AF:

0.164

Gnomad4 EAS exome

AF:

0.0176

Gnomad4 SAS exome

AF:

0.0979

Gnomad4 FIN exome

AF:

0.114

Gnomad4 NFE exome

AF:

0.136

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.186

AC:

28256

AN:

152164

Hom.:

3419

Cov.:

AF XY:

0.182

AC XY:

13536

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.338

Gnomad4 AMR

AF:

0.133

Gnomad4 ASJ

AF:

0.163

Gnomad4 EAS

AF:

0.0201

Gnomad4 SAS

AF:

0.102

Gnomad4 FIN

AF:

0.109

Gnomad4 NFE

AF:

0.138

Gnomad4 OTH

AF:

0.178

Alfa

AF:

0.166

Hom.:

674

Bravo

AF:

0.192

TwinsUK

AF:

0.132

AC:

488

ALSPAC

AF:

0.129

AC:

497

ESP6500AA

AF:

0.231

AC:

687

ESP6500EA

AF:

0.0989

AC:

664

ExAC

AF:

0.123

AC:

13916

Asia WGS

AF:

0.0890

AC:

312

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2013	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Pontoneocerebellar hypoplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Pontocerebellar hypoplasia type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

Cadd

Benign

Dann

Benign

0.92

DEOGEN2

Benign

0.016

Eigen

Benign

-0.073

Eigen_PC

Benign

-0.034

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.60

MetaRNN

Benign

0.00090

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

MutationTaster

Benign

0.017

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.5

REVEL

Benign

0.15

Sift

Benign

0.11

Sift4G

Benign

0.16

Polyphen

0.24

Vest4

0.097

MutPred

0.030

Gain of MoRF binding (P = 0.0899);

MPC

0.41

ClinPred

0.015

GERP RS

2.9

Varity_R

0.27

gMVP

0.12

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