3-12484689-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.-209G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 152,188 control chromosomes in the GnomAD database, including 24,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (24536 hom., cov: 33)
  • Exomes 𝑓: 0.50 (10 hom.)
• Consequence: TSEN2 NM_025265.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.48

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 (BayesDel_noAF=-0.97).
• BP6: Variant 3-12484689-G-T is Benign according to our data. Variant chr3-12484689-G-T is described in ClinVar as [Benign]. Clinvar id is 343059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSEN2	NM_025265.4	c.-209G>T		5_prime_UTR_variant	1/12	ENST00000284995.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSEN2	ENST00000284995.11	c.-209G>T		5_prime_UTR_variant	1/12	1	NM_025265.4	P2

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83137 AN: 151998 Hom.: 24507 Cov.: 33

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.499

Gnomad OTH AF: 0.543

GnomAD4 exome AF: 0.500 AC: 36 AN: 72 Hom.: 10 Cov.: 0 AF XY: 0.500 AC XY: 24 AN XY: 48

Gnomad4 AFR exome AF: 0.750

Gnomad4 ASJ exome AF: 1.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.547 AC: 83208 AN: 152116 Hom.: 24536 Cov.: 33 AF XY: 0.540 AC XY: 40095 AN XY: 74314

Gnomad4 AFR AF: 0.760

Gnomad4 AMR AF: 0.458

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.496

Gnomad4 NFE AF: 0.499

Gnomad4 OTH AF: 0.542

Alfa AF: 0.541 Hom.: 6894

Bravo AF: 0.553

Asia WGS AF: 0.322 AC: 1120 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2020

- -

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
BayesDel_noAF	Benign	-0.97
Cadd	Benign	0.66
Dann	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs709161; hg19: chr3-12526188;