NM_025265.4:c.-17-1099G>T

Variant names:

• chr3-12488685-G-T
• rs3856808
• NM_025265.4:c.-17-1099G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025265.4(TSEN2):​c.-17-1099G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0646 in 152,240 control chromosomes in the GnomAD database, including 696 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.065 (696 hom., cov: 32)
• Consequence: TSEN2 NM_025265.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	NM_025265.4	MANE Select	c.-17-1099G>T		intron	N/A	NP_079541.1
	TSEN2	NM_001321278.2		c.-17-1099G>T		intron	N/A	NP_001308207.1
	TSEN2	NM_001145392.2		c.-17-1099G>T		intron	N/A	NP_001138864.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.-17-1099G>T		intron	N/A	ENSP00000284995.6
	TSEN2	ENST00000402228.7	TSL:1	c.-17-1099G>T		intron	N/A	ENSP00000385976.3
	TSEN2	ENST00000454502.6	TSL:1	c.-17-1099G>T		intron	N/A	ENSP00000392029.2

Frequencies

GnomAD3 genomes AF: 0.0645 AC: 9813 AN: 152122 Hom.: 692 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.0684

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0371

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0714

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0646 AC: 9828 AN: 152240 Hom.: 696 Cov.: 32 AF XY: 0.0645 AC XY: 4800 AN XY: 74442

African (AFR) AF: 0.169 AC: 7004 AN: 41522

American (AMR) AF: 0.0684 AC: 1046 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.0374 AC: 194 AN: 5184

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4824

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0147 AC: 1003 AN: 68026

Other (OTH) AF: 0.0740 AC: 156 AN: 2108

Alfa AF: 0.00963 Hom.: 12

Bravo AF: 0.0726

Asia WGS AF: 0.100 AC: 346 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.16
DANN	Benign	0.56
PhyloP100		-1.4
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: rs3856808; hg19: chr3-12530184;