rs11559205

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_207346.3(TSEN54):c.409A>C(p.Ile137Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0724 in 1,613,612 control chromosomes in the GnomAD database, including 5,068 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 975 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4093 hom. )

Consequence

TSEN54
NM_207346.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.54

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 -16 ACMG points.

BP6

Variant 17-75517596-A-C is Benign according to our data. Variant chr17-75517596-A-C is described in ClinVar as Benign. ClinVar VariationId is 160134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.172 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSEN54	NM_207346.3 link	c.409A>C	p.Ile137Leu	missense_variant	Exon 5 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.409A>C	p.Ile137Leu	missense_variant	Exon 5 of 11	1	NM_207346.3	ENSP00000327487.6		Q7Z6J9-1

Frequencies

GnomAD3 genomes

AF:

0.0969

AC:

14715

AN:

151824

Hom.:

970

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.0757

Gnomad AMR

AF:

0.0753

Gnomad ASJ

AF:

0.0663

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0816

Gnomad FIN

AF:

0.0683

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0691

Gnomad OTH

AF:

0.0938

GnomAD2 exomes

AF:

0.0726

AC:

18249

AN:

251400

AF XY:

0.0727

show subpopulations

Gnomad AFR exome

AF:

0.177

Gnomad AMR exome

AF:

0.0641

Gnomad ASJ exome

AF:

0.0637

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0754

Gnomad NFE exome

AF:

0.0694

Gnomad OTH exome

AF:

0.0717

GnomAD4 exome

AF:

0.0699

AC:

102154

AN:

1461670

Hom.:

4093

Cov.:

AF XY:

0.0702

AC XY:

51078

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.188

AC:

6292

AN:

33478

American (AMR)

AF:

0.0669

AC:

2992

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0616

AC:

1611

AN:

26136

East Asian (EAS)

AF:

0.000378

AC:

AN:

39700

South Asian (SAS)

AF:

0.0842

AC:

7262

AN:

86254

European-Finnish (FIN)

AF:

0.0742

AC:

3951

AN:

53252

Middle Eastern (MID)

AF:

0.105

AC:

605

AN:

5768

European-Non Finnish (NFE)

AF:

0.0673

AC:

74816

AN:

1111968

Other (OTH)

AF:

0.0763

AC:

4610

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

5603

11206

16809

22412

28015

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2820

5640

8460

11280

14100

<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:

0.0970

AC:

14738

AN:

151942

Hom.:

975

Cov.:

AF XY:

0.0959

AC XY:

7118

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.175

AC:

7252

AN:

41396

American (AMR)

AF:

0.0752

AC:

1148

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0663

AC:

230

AN:

3470

East Asian (EAS)

AF:

0.000774

AC:

AN:

5166

South Asian (SAS)

AF:

0.0823

AC:

394

AN:

4786

European-Finnish (FIN)

AF:

0.0683

AC:

723

AN:

10580

Middle Eastern (MID)

AF:

0.0952

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0691

AC:

4694

AN:

67966

Other (OTH)

AF:

0.0928

AC:

196

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

635

1270

1906

2541

3176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0732

Hom.:

1464

Bravo

AF:

0.102

TwinsUK

AF:

0.0615

AC:

228

ALSPAC

AF:

0.0672

AC:

259

ESP6500AA

AF:

0.166

AC:

731

ESP6500EA

AF:

0.0674

AC:

580

ExAC

AF:

0.0748

AC:

9078

Asia WGS

AF:

0.0430

AC:

151

AN:

3478

EpiCase

AF:

0.0722

EpiControl

AF:

0.0709

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

Pontocerebellar hypoplasia type 2A

Benign:2

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Benign. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with pontocerebellar hypoplasia type 2A (MIM#277470) and type 4 (MIM#225753). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to leucine. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v2) at a frequency >=0.05 (19200 heterozygotes, 1035 homozygotes). (SB) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated endA superfamily domain (NCBI Conserved Domain). (I) 0805 - This variant has strong previous evidence of being benign in unrelated individuals. (ClinVar). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

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

0.29

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.026

.;T

Eigen

Benign

0.012

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.90

D;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

.;L

PhyloP100

1.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.11

Sift

Benign

0.16

T;D

Sift4G

Benign

0.17

T;D

Polyphen

0.97

.;D

Vest4

0.18

MPC

0.37

ClinPred

0.035

GERP RS

5.1

Varity_R

0.48

gMVP

0.38

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.37

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.37

Position offset: 6

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