rs33955793

Positions:

• chr3-12503330-G-A
• chr3-12503330-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.112

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]

ACMG classification

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	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	c.377G>A	p.Arg126His	missense_variant	5/12	1	NM_025265.4	P2

Frequencies

GnomAD3 genomes AF: 0.0720 AC: 10957 AN: 152128 Hom.: 522 Cov.: 32

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

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.: 32 AF XY: 0.0644 AC XY: 46830 AN XY: 727234

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.: 32 AF XY: 0.0728 AC XY: 5421 AN XY: 74444

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

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	T
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	N
LIST_S2	Benign	0.094	T;T;.;T;T;T
MetaRNN	Benign	0.0058	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs33955793; hg19: chr3-12544829; COSMIC: COSV53189027; COSMIC: COSV53189027;