chr3-12503592-T-C

Variant names:

• chr3-12503592-T-C
• rs3796329
• NM_025265.4:c.639T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 2B

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TSEN2	NM_025265.4	c.639T>C	p.Asp213Asp	synonymous_variant	Exon 5 of 12	ENST00000284995.11	NP_079541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995.11	c.639T>C	p.Asp213Asp	synonymous_variant	Exon 5 of 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

GnomAD2 exomes AF: 0.0247 AC: 5950 AN: 240472 AF XY: 0.0251

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 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

African (AFR) AF: 0.0313 AC: 1037 AN: 33120

American (AMR) AF: 0.0387 AC: 1699 AN: 43882

Ashkenazi Jewish (ASJ) AF: 0.00344 AC: 86 AN: 24978

East Asian (EAS) AF: 0.0436 AC: 1721 AN: 39476

South Asian (SAS) AF: 0.0554 AC: 4663 AN: 84238

European-Finnish (FIN) AF: 0.0102 AC: 539 AN: 52816

Middle Eastern (MID) AF: 0.0125 AC: 71 AN: 5682

European-Non Finnish (NFE) AF: 0.0129 AC: 14201 AN: 1102608

Other (OTH) AF: 0.0211 AC: 1261 AN: 59706

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

African (AFR) AF: 0.0334 AC: 1386 AN: 41534

American (AMR) AF: 0.0479 AC: 732 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.0373 AC: 193 AN: 5172

South Asian (SAS) AF: 0.0594 AC: 287 AN: 4828

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10628

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0138 AC: 937 AN: 68010

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0170 Hom.: 26

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 04, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Pontoneocerebellar hypoplasia Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3796329; hg19: chr3-12545091;