3-12503330-G-A

Position:

chr3-12503330-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_025265.4(TSEN2):c.377G>A(p.Arg126His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0675 in 1,614,116 control chromosomes in the GnomAD database, including 5,414 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. R126C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.072 ( 524 hom., cov: 32)

Exomes 𝑓: 0.067 ( 4890 hom. )

Consequence

TSEN2
NM_025265.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.112

Variant links:

Genes affected

TSEN2 (HGNC:28422): (tRNA splicing endonuclease subunit 2) This gene encodes one of the subunits of the tRNA splicing endonuclease. This endonuclease catalyzes the first step in RNA splicing which is the removal of introns. Mutations in this gene have been associated with pontocerebellar hypoplasia type 2. A pseudogene has been identified on chromosome 4. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]

TSEN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057552755).

BP6

Variant 3-12503330-G-A is Benign according to our data. Variant chr3-12503330-G-A is described in ClinVar as [Benign]. Clinvar id is 96175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-12503330-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN2	NM_025265.4 linkuse as main transcript	c.377G>A	p.Arg126His	missense_variant	5/12	ENST00000284995.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN2	ENST00000284995.11 linkuse as main transcript	c.377G>A	p.Arg126His	missense_variant	5/12	1	NM_025265.4	P2	Q8NCE0-1

Frequencies

GnomAD3 genomes

AF:

0.0720

AC:

10957

AN:

152128

Hom.:

522

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0664

Gnomad AMI

AF:

0.0998

Gnomad AMR

AF:

0.160

Gnomad ASJ

AF:

0.0351

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0354

Gnomad FIN

AF:

0.0768

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0640

Gnomad OTH

AF:

0.0621

GnomAD3 exomes

AF:

0.0873

AC:

21940

AN:

251324

Hom.:

2142

AF XY:

0.0773

AC XY:

10504

AN XY:

135834

show subpopulations

Gnomad AFR exome

AF:

0.0640

Gnomad AMR exome

AF:

0.298

Gnomad ASJ exome

AF:

0.0366

Gnomad EAS exome

AF:

0.0133

Gnomad SAS exome

AF:

0.0311

Gnomad FIN exome

AF:

0.0771

Gnomad NFE exome

AF:

0.0606

Gnomad OTH exome

AF:

0.0794

GnomAD4 exome

AF:

0.0670

AC:

97900

AN:

1461870

Hom.:

4890

Cov.:

AF XY:

0.0644

AC XY:

46830

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0641

Gnomad4 AMR exome

AF:

0.280

Gnomad4 ASJ exome

AF:

0.0374

Gnomad4 EAS exome

AF:

0.0128

Gnomad4 SAS exome

AF:

0.0334

Gnomad4 FIN exome

AF:

0.0772

Gnomad4 NFE exome

AF:

0.0638

Gnomad4 OTH exome

AF:

0.0609

GnomAD4 genome

AF:

0.0721

AC:

10973

AN:

152246

Hom.:

524

Cov.:

AF XY:

0.0728

AC XY:

5421

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0665

Gnomad4 AMR

AF:

0.160

Gnomad4 ASJ

AF:

0.0351

Gnomad4 EAS

AF:

0.0160

Gnomad4 SAS

AF:

0.0354

Gnomad4 FIN

AF:

0.0768

Gnomad4 NFE

AF:

0.0640

Gnomad4 OTH

AF:

0.0620

Alfa

AF:

0.0565

Hom.:

220

Bravo

AF:

0.0809

ESP6500AA

AF:

0.0608

AC:

268

ESP6500EA

AF:

0.0662

AC:

569

ExAC

AF:

0.0778

AC:

9444

EpiCase

AF:

0.0544

EpiControl

AF:

0.0546

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 09, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

1.3

DANN

Benign

0.85

DEOGEN2

Benign

0.023

T;.;T;.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.094

T;T;.;T;T;T

MetaRNN

Benign

0.0058

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.29

.;N;N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

0.66

N;N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.37

T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;T

Polyphen

0.0010

.;.;B;.;B;B

Vest4

0.14, 0.036, 0.035, 0.034

MPC

0.034

ClinPred

0.0065

GERP RS

-9.2

Varity_R

0.012

gMVP

0.17

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

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