NM_025265.4:c.-353G>T

Variant names:

• chr3-12484545-G-T
• rs1023680154
• NM_025265.4:c.-353G>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_025265.4(TSEN2):​c.-353G>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 0.000768 in 152,382 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00077 (1 hom., cov: 33)
• Consequence: TSEN2 NM_025265.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000768 (117/152382) while in subpopulation AFR AF = 0.00264 (110/41598). AF 95% confidence interval is 0.00224. There are 1 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025265.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	NM_025265.4	MANE Select	c.-353G>T		5_prime_UTR	Exon 1 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001145392.2		c.-101G>T		5_prime_UTR	Exon 1 of 12	NP_001138864.1	Q8NCE0-1
	TSEN2	NM_001321279.2		c.-353G>T		5_prime_UTR	Exon 1 of 11	NP_001308208.1	Q8NCE0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.-353G>T		5_prime_UTR	Exon 1 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.-101G>T		5_prime_UTR	Exon 1 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.-18+28G>T		intron	N/A	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.000768 AC: 117 AN: 152264 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152382 Hom.: 1 Cov.: 33 AF XY: 0.000845 AC XY: 63 AN XY: 74514

African (AFR) AF: 0.00264 AC: 110 AN: 41598

American (AMR) AF: 0.000261 AC: 4 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000971

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.69
PhyloP100		0.10
PromoterAI		-0.12	Neutral
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

Other links and lift over

dbSNP: rs1023680154; hg19: chr3-12526044;