17-75522122-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K347Y) has been classified as Uncertain significance.

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

Publications

38 publications found

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 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 2A
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
pontocerebellar hypoplasia type 4
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
pontocerebellar hypoplasia type 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TSEN54 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 160123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
TSEN54	NM_207346.3 link	c.1041G>C	p.Lys347Asn	missense_variant	Exon 8 of 11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11 link	c.1041G>C	p.Lys347Asn	missense_variant	Exon 8 of 11	1	NM_207346.3	ENSP00000327487.6

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

GnomAD2 exomes

AF:

0.585

AC:

111104

AN:

189948

AF XY:

0.606

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 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

African (AFR)

AF:

0.184

AC:

5958

AN:

32330

American (AMR)

AF:

0.383

AC:

15189

AN:

39682

Ashkenazi Jewish (ASJ)

AF:

0.588

AC:

14949

AN:

25436

East Asian (EAS)

AF:

0.455

AC:

16876

AN:

37106

South Asian (SAS)

AF:

0.666

AC:

54262

AN:

81476

European-Finnish (FIN)

AF:

0.697

AC:

34540

AN:

49528

Middle Eastern (MID)

AF:

0.623

AC:

3561

AN:

5716

European-Non Finnish (NFE)

AF:

0.704

AC:

768199

AN:

1090436

Other (OTH)

AF:

0.628

AC:

36926

AN:

58828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

20041

40082

60123

80164

100205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19334

38668

58002

77336

96670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.527

AC:

80270

AN:

152176

Hom.:

24673

Cov.:

AF XY:

0.529

AC XY:

39368

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.210

AC:

8718

AN:

41530

American (AMR)

AF:

0.462

AC:

7067

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.599

AC:

2081

AN:

3472

East Asian (EAS)

AF:

0.461

AC:

2385

AN:

5178

South Asian (SAS)

AF:

0.647

AC:

3126

AN:

4832

European-Finnish (FIN)

AF:

0.707

AC:

7485

AN:

10592

Middle Eastern (MID)

AF:

0.602

AC:

177

AN:

294

European-Non Finnish (NFE)

AF:

0.696

AC:

47332

AN:

67972

Other (OTH)

AF:

0.543

AC:

1146

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1675

3350

5025

6700

8375

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

702

1404

2106

2808

3510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.641

Hom.:

10545

Bravo

AF:

0.491

TwinsUK

AF:

0.708

AC:

2624

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 08, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:4

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Pontocerebellar hypoplasia type 4

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pontocerebellar hypoplasia type 2A

Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pontoneocerebellar hypoplasia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.083

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0000042

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.8

PhyloP100

3.9

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.4

Sift

Benign

0.047

Sift4G

Uncertain

0.0060

Vest4

0.19

ClinPred

0.032

GERP RS

4.5

Varity_R

0.32

gMVP

0.44

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over