rs78685815

Variant names:

• chr3-12489962-G-A
• rs78685815
• NM_025265.4:c.162G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-12489962-G-A
• chr3-12489962-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_025265.4(TSEN2):​c.162G>A​(p.Ala54Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0261 in 1,613,972 control chromosomes in the GnomAD database, including 1,739 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A54A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.065 (702 hom., cov: 32)
  • Exomes 𝑓: 0.022 (1037 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.64
• Publications: 9 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 3-12489962-G-A is Benign according to our data. Variant chr3-12489962-G-A is described in ClinVar as Benign. ClinVar VariationId is 137753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 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.162G>A	p.Ala54Ala	synonymous	Exon 2 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.162G>A	p.Ala54Ala	synonymous	Exon 2 of 12	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.162G>A	p.Ala54Ala	synonymous	Exon 2 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.162G>A	p.Ala54Ala	synonymous	Exon 2 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.162G>A	p.Ala54Ala	synonymous	Exon 2 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.162G>A	p.Ala54Ala	synonymous	Exon 2 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.0647 AC: 9842 AN: 152120 Hom.: 698 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0694

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.0371

Gnomad SAS AF: 0.0605

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.0723

GnomAD2 exomes AF: 0.0354 AC: 8910 AN: 251370 AF XY: 0.0329

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0446

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0338

Gnomad FIN exome AF: 0.00971

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0324

GnomAD4 exome AF: 0.0221 AC: 32341 AN: 1461734 Hom.: 1037 Cov.: 32 AF XY: 0.0221 AC XY: 16090 AN XY: 727164

African (AFR) AF: 0.174 AC: 5834 AN: 33450

American (AMR) AF: 0.0488 AC: 2181 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26136

East Asian (EAS) AF: 0.0437 AC: 1734 AN: 39698

South Asian (SAS) AF: 0.0558 AC: 4811 AN: 86250

European-Finnish (FIN) AF: 0.0102 AC: 547 AN: 53402

Middle Eastern (MID) AF: 0.0246 AC: 142 AN: 5768

European-Non Finnish (NFE) AF: 0.0136 AC: 15096 AN: 1111922

Other (OTH) AF: 0.0314 AC: 1898 AN: 60384

GnomAD4 genome AF: 0.0648 AC: 9859 AN: 152238 Hom.: 702 Cov.: 32 AF XY: 0.0646 AC XY: 4806 AN XY: 74434

African (AFR) AF: 0.169 AC: 7015 AN: 41508

American (AMR) AF: 0.0694 AC: 1061 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.0373 AC: 193 AN: 5170

South Asian (SAS) AF: 0.0597 AC: 288 AN: 4822

European-Finnish (FIN) AF: 0.0107 AC: 113 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0148 AC: 1005 AN: 68044

Other (OTH) AF: 0.0758 AC: 160 AN: 2110

Alfa AF: 0.0265 Hom.: 295

Bravo AF: 0.0727

Asia WGS AF: 0.122 AC: 424 AN: 3478

EpiCase AF: 0.0157

EpiControl AF: 0.0172

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Pontoneocerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.52
DANN	Benign	0.67
PhyloP100		-3.6
PromoterAI		-0.058	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78685815; hg19: chr3-12531461; COSMIC: COSV53191301;