rs11559205

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The ENST00000333213.11(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. 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
ENST00000333213.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 160134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75517596-A-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TSEN54	NM_207346.3 linkuse as main transcript	c.409A>C	p.Ile137Leu	missense_variant	5/11	ENST00000333213.11	NP_997229.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN54	ENST00000333213.11 linkuse as main transcript	c.409A>C	p.Ile137Leu	missense_variant	5/11	1	NM_207346.3	ENSP00000327487	P1	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

GnomAD3 exomes

AF:

0.0726

AC:

18249

AN:

251400

Hom.:

844

AF XY:

0.0727

AC XY:

9876

AN XY:

135878

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 SAS exome

AF:

0.0828

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

Gnomad4 AFR exome

AF:

0.188

Gnomad4 AMR exome

AF:

0.0669

Gnomad4 ASJ exome

AF:

0.0616

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0842

Gnomad4 FIN exome

AF:

0.0742

Gnomad4 NFE exome

AF:

0.0673

Gnomad4 OTH exome

AF:

0.0763

GnomAD4 genome

AF:

0.0970

AC:

14738

AN:

151942

Hom.:

975

Cov.:

AF XY:

0.0959

AC XY:

7118

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.175

Gnomad4 AMR

AF:

0.0752

Gnomad4 ASJ

AF:

0.0663

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.0823

Gnomad4 FIN

AF:

0.0683

Gnomad4 NFE

AF:

0.0691

Gnomad4 OTH

AF:

0.0928

Alfa

AF:

0.0691

Hom.:

527

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	- -

Pontocerebellar hypoplasia type 2A

Benign:2

Benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	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 -
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

- -

Pontocerebellar hypoplasia type 4

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

Benign

0.29

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

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

MutationTaster

Benign

0.00022

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

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

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