NM_207346.3:c.1310C>T

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.1310C>T(p.Ala437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,613,570 control chromosomes in the GnomAD database, including 372,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. A437I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.64 ( 31161 hom., cov: 31)

Exomes 𝑓: 0.68 ( 341242 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.442

Publications

48 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=4.8462252E-6).

BP6

Variant 17-75523332-C-T is Benign according to our data. Variant chr17-75523332-C-T is described in ClinVar as [Benign]. Clinvar id is 160127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSEN54	NM_207346.3 link	c.1310C>T	p.Ala437Val	missense_variant	Exon 9 of 11	ENST00000333213.11	NP_997229.2	Q7Z6J9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11 link	c.1310C>T	p.Ala437Val	missense_variant	Exon 9 of 11	1	NM_207346.3	ENSP00000327487.6		Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.635

AC:

96395

AN:

151732

Hom.:

31158

Cov.:

show subpopulations

Gnomad AFR

AF:

0.580

Gnomad AMI

AF:

0.828

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.606

Gnomad EAS

AF:

0.457

Gnomad SAS

AF:

0.648

Gnomad FIN

AF:

0.708

Gnomad MID

AF:

0.622

Gnomad NFE

AF:

0.698

Gnomad OTH

AF:

0.627

GnomAD2 exomes

AF:

0.617

AC:

155045

AN:

251440

AF XY:

0.632

show subpopulations

Gnomad AFR exome

AF:

0.582

Gnomad AMR exome

AF:

0.389

Gnomad ASJ exome

AF:

0.592

Gnomad EAS exome

AF:

0.439

Gnomad FIN exome

AF:

0.698

Gnomad NFE exome

AF:

0.692

Gnomad OTH exome

AF:

0.634

GnomAD4 exome

AF:

0.679

AC:

992514

AN:

1461720

Hom.:

341242

Cov.:

AF XY:

0.680

AC XY:

494720

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.568

AC:

19023

AN:

33472

American (AMR)

AF:

0.404

AC:

18089

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.593

AC:

15503

AN:

26134

East Asian (EAS)

AF:

0.453

AC:

17987

AN:

39698

South Asian (SAS)

AF:

0.667

AC:

57517

AN:

86256

European-Finnish (FIN)

AF:

0.697

AC:

37212

AN:

53368

Middle Eastern (MID)

AF:

0.639

AC:

3687

AN:

5766

European-Non Finnish (NFE)

AF:

0.705

AC:

784003

AN:

1111916

Other (OTH)

AF:

0.654

AC:

39493

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

19317

38634

57950

77267

96584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19652

39304

58956

78608

98260

<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:

0.635

AC:

96426

AN:

151850

Hom.:

31161

Cov.:

AF XY:

0.633

AC XY:

46956

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.579

AC:

23955

AN:

41362

American (AMR)

AF:

0.508

AC:

7749

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.606

AC:

2101

AN:

3466

East Asian (EAS)

AF:

0.456

AC:

2359

AN:

5168

South Asian (SAS)

AF:

0.647

AC:

3109

AN:

4802

European-Finnish (FIN)

AF:

0.708

AC:

7461

AN:

10544

Middle Eastern (MID)

AF:

0.631

AC:

183

AN:

290

European-Non Finnish (NFE)

AF:

0.698

AC:

47437

AN:

67950

Other (OTH)

AF:

0.626

AC:

1317

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1731

3462

5192

6923

8654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

796

1592

2388

3184

3980

<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:

0.665

Hom.:

151276

Bravo

AF:

0.614

TwinsUK

AF:

0.709

AC:

2630

ALSPAC

AF:

0.714

AC:

2751

ESP6500AA

AF:

0.580

AC:

2557

ESP6500EA

AF:

0.702

AC:

6036

ExAC

AF:

0.624

AC:

75760

Asia WGS

AF:

0.563

AC:

1958

AN:

3478

EpiCase

AF:

0.682

EpiControl

AF:

0.681

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

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

- -

not provided

Benign:4

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

- -

Apr 20, 2017

Athena Diagnostics

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

- -

Pontocerebellar hypoplasia type 4

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

Benign

0.097

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.022

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0000048

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

PhyloP100

0.44

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

REVEL

Benign

0.10

Sift

Benign

0.49

Sift4G

Benign

0.14

Polyphen

0.70

Vest4

0.027

MPC

0.26

ClinPred

0.013

GERP RS

0.51

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.018

gMVP

0.25

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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