rs144662042

Positions:

chr17-75524299-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_207346.3(TSEN54):c.1468C>T(p.Arg490Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,614,166 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 31 hom., cov: 32)

Exomes 𝑓: 0.015 ( 233 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.43

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:

TSEN54 (HGNC:):

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=0.005048424).

BP6

Variant 17-75524299-C-T is Benign according to our data. Variant chr17-75524299-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 160130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75524299-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1974/152324) while in subpopulation NFE AF= 0.0192 (1305/68034). AF 95% confidence interval is 0.0183. There are 31 homozygotes in gnomad4. There are 990 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3 linkuse as main transcript	c.1468C>T	p.Arg490Trp	missense_variant	11/11	ENST00000333213.11	NP_997229.2	Q7Z6J9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11 linkuse as main transcript	c.1468C>T	p.Arg490Trp	missense_variant	11/11	1	NM_207346.3	ENSP00000327487.6		Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1974

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00328

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.00373

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0329

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0192

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.0123

AC:

3096

AN:

251452

Hom.:

AF XY:

0.0124

AC XY:

1684

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00232

Gnomad FIN exome

AF:

0.0332

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0153

AC:

22301

AN:

1461842

Hom.:

233

Cov.:

AF XY:

0.0150

AC XY:

10932

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.00444

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00319

Gnomad4 FIN exome

AF:

0.0346

Gnomad4 NFE exome

AF:

0.0171

Gnomad4 OTH exome

AF:

0.0127

GnomAD4 genome

AF:

0.0130

AC:

1974

AN:

152324

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

990

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00327

Gnomad4 AMR

AF:

0.00372

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.0329

Gnomad4 NFE

AF:

0.0192

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0138

AC:

ALSPAC

AF:

0.0156

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0171

AC:

147

ExAC

AF:

0.0132

AC:

1605

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2016	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:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

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

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.19

Sift

Benign

0.034

Sift4G

Benign

0.12

Polyphen

1.0

Vest4

0.14

MPC

0.86

ClinPred

0.029

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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