17-75522122-G-C

Position:

chr17-75522122-G-C

Variant summary

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

The NM_207346.3(TSEN54):c.1041G>C(p.Lys347Asn) variant causes a missense change. The variant allele was found at a frequency of 0.655 in 1,572,714 control chromosomes in the GnomAD database, including 350,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 24673 hom., cov: 33)

Exomes 𝑓: 0.67 ( 325821 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 3.94

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=4.242469E-6).

BP6

Variant 17-75522122-G-C is Benign according to our data. Variant chr17-75522122-G-C is described in ClinVar as [Benign]. Clinvar id is 160123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75522122-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.691 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.1041G>C	p.Lys347Asn	missense_variant	8/11	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.1041G>C	p.Lys347Asn	missense_variant	8/11	1	NM_207346.3	ENSP00000327487.6		Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.528

AC:

80268

AN:

152058

Hom.:

24678

Cov.:

show subpopulations

Gnomad AFR

AF:

0.210

Gnomad AMI

AF:

0.827

Gnomad AMR

AF:

0.462

Gnomad ASJ

AF:

0.599

Gnomad EAS

AF:

0.461

Gnomad SAS

AF:

0.647

Gnomad FIN

AF:

0.707

Gnomad MID

AF:

0.595

Gnomad NFE

AF:

0.696

Gnomad OTH

AF:

0.543

GnomAD3 exomes

AF:

0.585

AC:

111104

AN:

189948

Hom.:

34814

AF XY:

0.606

AC XY:

62111

AN XY:

102432

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.371

Gnomad ASJ exome

AF:

0.585

Gnomad EAS exome

AF:

0.434

Gnomad SAS exome

AF:

0.666

Gnomad FIN exome

AF:

0.698

Gnomad NFE exome

AF:

0.690

Gnomad OTH exome

AF:

0.613

GnomAD4 exome

AF:

0.669

AC:

950460

AN:

1420538

Hom.:

325821

Cov.:

AF XY:

0.672

AC XY:

471759

AN XY:

702484

show subpopulations

Gnomad4 AFR exome

AF:

0.184

Gnomad4 AMR exome

AF:

0.383

Gnomad4 ASJ exome

AF:

0.588

Gnomad4 EAS exome

AF:

0.455

Gnomad4 SAS exome

AF:

0.666

Gnomad4 FIN exome

AF:

0.697

Gnomad4 NFE exome

AF:

0.704

Gnomad4 OTH exome

AF:

0.628

GnomAD4 genome

AF:

0.527

AC:

80270

AN:

152176

Hom.:

24673

Cov.:

AF XY:

0.529

AC XY:

39368

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.210

Gnomad4 AMR

AF:

0.462

Gnomad4 ASJ

AF:

0.599

Gnomad4 EAS

AF:

0.461

Gnomad4 SAS

AF:

0.647

Gnomad4 FIN

AF:

0.707

Gnomad4 NFE

AF:

0.696

Gnomad4 OTH

AF:

0.543

Alfa

AF:

0.641

Hom.:

10545

Bravo

AF:

0.491

TwinsUK

AF:

0.708

AC:

2624

ALSPAC

AF:

0.713

AC:

2747

ESP6500AA

AF:

0.230

AC:

1008

ESP6500EA

AF:

0.699

AC:

5988

ExAC

AF:

0.542

AC:

63557

Asia WGS

AF:

0.540

AC:

1877

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pontocerebellar hypoplasia type 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Pontocerebellar hypoplasia type 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

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. -

Pontocerebellar hypoplasia type 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.083

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0000042

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.12

Sift

Benign

0.047

Sift4G

Uncertain

0.0060

Polyphen

0.97

Vest4

0.19

MutPred

0.25

Gain of ubiquitination at K345 (P = 0.028);

MPC

0.83

ClinPred

0.032

GERP RS

4.5

Varity_R

0.32

gMVP

0.44

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