3-12484699-G-T

Variant names:

• chr3-12484699-G-T
• rs41293381
• NM_025265.4:c.-199G>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.-199G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 152,416 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (39 hom., cov: 33)
  • Exomes 𝑓: 0.026 (0 hom.)
• Consequence: TSEN2 NM_025265.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.302

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=-0.87).
• BP6: Variant 3-12484699-G-T is Benign according to our data. Variant chr3-12484699-G-T is described in ClinVar as [Benign]. Clinvar id is 343062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.-199G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	ENST00000284995.11	NP_079541.1
TSEN2	NM_025265.4	c.-199G>T		5_prime_UTR_variant	Exon 1 of 12	ENST00000284995.11	NP_079541.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSEN2	ENST00000284995	c.-199G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12	1	NM_025265.4	ENSP00000284995.6
TSEN2	ENST00000284995	c.-199G>T		5_prime_UTR_variant	Exon 1 of 12	1	NM_025265.4	ENSP00000284995.6

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2435 AN: 152220 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.00581

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0288

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0287

GnomAD4 exome AF: 0.0256 AC: 2 AN: 78 Hom.: 0 Cov.: 0 AF XY: 0.0385 AC XY: 2 AN XY: 52

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0179

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0160 AC: 2442 AN: 152338 Hom.: 39 Cov.: 33 AF XY: 0.0176 AC XY: 1312 AN XY: 74480

Gnomad4 AFR AF: 0.00582

Gnomad4 AMR AF: 0.0431

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.0291

Gnomad4 SAS AF: 0.0595

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0127 Hom.: 2

Bravo AF: 0.0166

Asia WGS AF: 0.0870 AC: 303 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

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	-0.87
CADD	Benign	5.2
DANN	Benign	0.58

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: rs41293381; hg19: chr3-12526198;