3-12489922-G-A

Position:

chr3-12489922-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.122G>A(p.Arg41His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 1,613,910 control chromosomes in the GnomAD database, including 1,734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.065 ( 698 hom., cov: 32)

Exomes 𝑓: 0.022 ( 1036 hom. )

Consequence

TSEN2
NM_025265.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.262

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=0.001170665).

BP6

Variant 3-12489922-G-A is Benign according to our data. Variant chr3-12489922-G-A is described in ClinVar as [Benign]. Clinvar id is 137752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-12489922-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN2	NM_025265.4 linkuse as main transcript	c.122G>A	p.Arg41His	missense_variant	2/12	ENST00000284995.11	NP_079541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995.11 linkuse as main transcript	c.122G>A	p.Arg41His	missense_variant	2/12	1	NM_025265.4	ENSP00000284995	P2	Q8NCE0-1

Frequencies

GnomAD3 genomes

AF:

0.0646

AC:

9828

AN:

152054

Hom.:

694

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0687

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.0374

Gnomad SAS

AF:

0.0607

Gnomad FIN

AF:

0.0107

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0725

GnomAD3 exomes

AF:

0.0354

AC:

8907

AN:

251432

Hom.:

390

AF XY:

0.0329

AC XY:

4475

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.172

Gnomad AMR exome

AF:

0.0446

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.0338

Gnomad SAS exome

AF:

0.0578

Gnomad FIN exome

AF:

0.00971

Gnomad NFE exome

AF:

0.0152

Gnomad OTH exome

AF:

0.0318

GnomAD4 exome

AF:

0.0221

AC:

32265

AN:

1461738

Hom.:

1036

Cov.:

AF XY:

0.0221

AC XY:

16058

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.175

Gnomad4 AMR exome

AF:

0.0488

Gnomad4 ASJ exome

AF:

0.00375

Gnomad4 EAS exome

AF:

0.0436

Gnomad4 SAS exome

AF:

0.0556

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.0136

Gnomad4 OTH exome

AF:

0.0305

GnomAD4 genome

AF:

0.0647

AC:

9843

AN:

152172

Hom.:

698

Cov.:

AF XY:

0.0646

AC XY:

4811

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.169

Gnomad4 AMR

AF:

0.0687

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.0377

Gnomad4 SAS

AF:

0.0600

Gnomad4 FIN

AF:

0.0107

Gnomad4 NFE

AF:

0.0147

Gnomad4 OTH

AF:

0.0750

Alfa

AF:

0.0215

Hom.:

165

Bravo

AF:

0.0727

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.159

AC:

699

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.0381

AC:

4628

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.0158

EpiControl

AF:

0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2014	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Pontoneocerebellar hypoplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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

0.062

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.6

DANN

Benign

0.93

DEOGEN2

Benign

0.027

T;.;T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.45

T;T;.;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

.;L;L;L;L;L

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P

PrimateAI

Benign

0.21

PROVEAN

Uncertain

-2.4

N;N;N;N;N;N

REVEL

Benign

0.050

Sift

Benign

0.10

T;T;T;T;T;T

Sift4G

Benign

0.48

T;T;T;T;T;T

Polyphen

0.033, 0.074

.;.;B;.;B;B

Vest4

0.032, 0.028

MPC

0.035

ClinPred

0.0067

GERP RS

-1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.027

gMVP

0.39

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