rs3796329

Positions:

• chr3-12503592-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025265.4(TSEN2):​c.639T>C​(p.Asp213Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,598,752 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (66 hom., cov: 32)
  • Exomes 𝑓: 0.017 (435 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.813

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 3-12503592-T-C is Benign according to our data. Variant chr3-12503592-T-C is described in ClinVar as [Benign]. Clinvar id is 137750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.813 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSEN2	NM_025265.4	c.639T>C	p.Asp213Asp	synonymous_variant	5/12	ENST00000284995.11	NP_079541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995.11	c.639T>C	p.Asp213Asp	synonymous_variant	5/12	1	NM_025265.4	ENSP00000284995.6

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3741 AN: 152128 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0479

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.0374

GnomAD3 exomes AF: 0.0247 AC: 5950 AN: 240472 Hom.: 128 AF XY: 0.0251 AC XY: 3249 AN XY: 129504

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.0360

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.0339

Gnomad SAS exome AF: 0.0588

Gnomad FIN exome AF: 0.00963

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0250

GnomAD4 exome AF: 0.0175 AC: 25278 AN: 1446506 Hom.: 435 Cov.: 32 AF XY: 0.0182 AC XY: 13035 AN XY: 717518

Gnomad4 AFR exome AF: 0.0313

Gnomad4 AMR exome AF: 0.0387

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.0436

Gnomad4 SAS exome AF: 0.0554

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0211

GnomAD4 genome AF: 0.0247 AC: 3753 AN: 152246 Hom.: 66 Cov.: 32 AF XY: 0.0261 AC XY: 1940 AN XY: 74452

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.0479

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0373

Gnomad4 SAS AF: 0.0594

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0156 Hom.: 12

Bravo AF: 0.0259

Asia WGS AF: 0.113 AC: 393 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Jan 29, 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 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
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.85
DANN	Benign	0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3796329; hg19: chr3-12545091;