chr3-12532673-G-A

Variant names:

• chr3-12532673-G-A
• rs116627250
• NM_025265.4:c.1350G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_025265.4(TSEN2):​c.1350G>A​(p.Leu450Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,082 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.889
• 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]

MKRN2OS (HGNC:40375): (MKRN2 opposite strand)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-12532673-G-A is Benign according to our data. Variant chr3-12532673-G-A is described in ClinVar as Benign. ClinVar VariationId is 160107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.889 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0127 (1935/152226) while in subpopulation AFR AF = 0.0434 (1802/41526). AF 95% confidence interval is 0.0417. There are 43 homozygotes in GnomAd4. There are 933 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 43 AR gene

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.1350G>A	p.Leu450Leu	synonymous	Exon 12 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001145392.2		c.1350G>A	p.Leu450Leu	synonymous	Exon 12 of 12	NP_001138864.1	Q8NCE0-1
	TSEN2	NM_001321277.2		c.1350G>A	p.Leu450Leu	synonymous	Exon 12 of 12	NP_001308206.1	Q8NCE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSEN2	ENST00000284995.11	TSL:1 MANE Select	c.1350G>A	p.Leu450Leu	synonymous	Exon 12 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.1350G>A	p.Leu450Leu	synonymous	Exon 12 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.1173G>A	p.Leu391Leu	synonymous	Exon 13 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1933 AN: 152108 Hom.: 43 Cov.: 33

Gnomad AFR AF: 0.0434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00328 AC: 825 AN: 251378 AF XY: 0.00231

Gnomad AFR exome AF: 0.0438

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00132 AC: 1936 AN: 1461856 Hom.: 31 Cov.: 31 AF XY: 0.00106 AC XY: 773 AN XY: 727238

African (AFR) AF: 0.0436 AC: 1460 AN: 33470

American (AMR) AF: 0.00293 AC: 131 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111996

Other (OTH) AF: 0.00255 AC: 154 AN: 60396

GnomAD4 genome AF: 0.0127 AC: 1935 AN: 152226 Hom.: 43 Cov.: 33 AF XY: 0.0125 AC XY: 933 AN XY: 74428

African (AFR) AF: 0.0434 AC: 1802 AN: 41526

American (AMR) AF: 0.00680 AC: 104 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.00604 Hom.: 14

Bravo AF: 0.0150

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Pontoneocerebellar hypoplasia (1)
-	-	1	TSEN2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.41
DANN	Benign	0.85
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs116627250; hg19: chr3-12574172;