rs8079373

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.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. 14/21 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:12

Conservation

PhyloP100: 0.442

Publications

20 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=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.

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 rank	MANE	Protein	UniProt
TSEN54	NM_207346.3 link	c.114T>G	p.His38Gln	missense_variant	Exon 2 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.114T>G	p.His38Gln	missense_variant	Exon 2 of 11	1	NM_207346.3	ENSP00000327487.6		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

GnomAD2 exomes

AF:

0.121

AC:

25375

AN:

210344

AF XY:

0.120

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 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

African (AFR)

AF:

0.349

AC:

11179

AN:

32062

American (AMR)

AF:

0.0866

AC:

3830

AN:

44208

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

4233

AN:

25776

East Asian (EAS)

AF:

0.0176

AC:

685

AN:

38940

South Asian (SAS)

AF:

0.0979

AC:

8343

AN:

85262

European-Finnish (FIN)

AF:

0.114

AC:

4274

AN:

37576

Middle Eastern (MID)

AF:

0.155

AC:

881

AN:

5698

European-Non Finnish (NFE)

AF:

0.136

AC:

150133

AN:

1105658

Other (OTH)

AF:

0.136

AC:

8102

AN:

59572

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

9636

19273

28909

38546

48182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5322

10644

15966

21288

26610

<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:

0.186

AC:

28256

AN:

152164

Hom.:

3419

Cov.:

AF XY:

0.182

AC XY:

13536

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.338

AC:

14050

AN:

41534

American (AMR)

AF:

0.133

AC:

2038

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

567

AN:

3472

East Asian (EAS)

AF:

0.0201

AC:

104

AN:

5178

South Asian (SAS)

AF:

0.102

AC:

491

AN:

4832

European-Finnish (FIN)

AF:

0.109

AC:

1153

AN:

10582

Middle Eastern (MID)

AF:

0.192

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.138

AC:

9402

AN:

67962

Other (OTH)

AF:

0.178

AC:

375

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1154

2308

3462

4616

5770

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.169

Hom.:

721

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:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

May 07, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Oct 31, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pontoneocerebellar hypoplasia

Benign:1

Jan 12, 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 4

Benign:1

May 28, 2019

Mendelics

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

0.49

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

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

PhyloP100

0.44

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

PromoterAI

0.093

Neutral

(source)

Varity_R

0.27

gMVP

0.12

Mutation Taster

=92/8

polymorphism (auto)

(source)

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

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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