rs3806662

Variant names:

• chr3-12484507-G-A
• rs3806662
• NM_025265.4:c.-391G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_025265.4(TSEN2):​c.-391G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 152,144 control chromosomes in the GnomAD database, including 778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (778 hom., cov: 33)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: TSEN2 NM_025265.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.173
• Publications: 14 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, PanelApp Australia
• pontocerebellar hypoplasia type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 3-12484507-G-A is Benign according to our data. Variant chr3-12484507-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.164 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	NM_025265.4	MANE Select	c.-391G>A		5_prime_UTR	Exon 1 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.-28G>A		5_prime_UTR	Exon 1 of 12	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.-139G>A		5_prime_UTR	Exon 1 of 12	NP_001138864.1	Q8NCE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.-391G>A		5_prime_UTR	Exon 1 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.-139G>A		5_prime_UTR	Exon 1 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.-28G>A		5_prime_UTR	Exon 1 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13516 AN: 152016 Hom.: 776 Cov.: 33

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.0160

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.0765

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0647

Gnomad OTH AF: 0.0732

GnomAD4 exome AF: 0.143 AC: 2 AN: 14 Hom.: 0 Cov.: 0 AF XY: 0.100 AC XY: 1 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 2 AN: 12

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0890 AC: 13543 AN: 152130 Hom.: 778 Cov.: 33 AF XY: 0.0893 AC XY: 6641 AN XY: 74380

African (AFR) AF: 0.122 AC: 5062 AN: 41370

American (AMR) AF: 0.169 AC: 2591 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3470

East Asian (EAS) AF: 0.0160 AC: 83 AN: 5188

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4834

European-Finnish (FIN) AF: 0.0765 AC: 813 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0646 AC: 4398 AN: 68028

Other (OTH) AF: 0.0729 AC: 154 AN: 2112

Alfa AF: 0.0737 Hom.: 628

Bravo AF: 0.101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.3
DANN	Benign	0.89
PhyloP100		0.17
PromoterAI		-0.14	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs3806662; hg19: chr3-12526006;