3-12516569-A-G

Variant names:

• chr3-12516569-A-G
• rs12491241
• NM_025265.4:c.910-42A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_025265.4(TSEN2):​c.910-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,606,704 control chromosomes in the GnomAD database, including 315 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (42 hom., cov: 31)
  • Exomes 𝑓: 0.015 (273 hom.)
• Consequence: TSEN2 NM_025265.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.208
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-12516569-A-G is Benign according to our data. Variant chr3-12516569-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1214522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0178 (2702/151832) while in subpopulation AMR AF = 0.0457 (696/15226). AF 95% confidence interval is 0.0429. There are 42 homozygotes in GnomAd4. There are 1396 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 42 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.910-42A>G		intron	N/A	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.910-42A>G		intron	N/A	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.910-42A>G		intron	N/A	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.910-42A>G		intron	N/A	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.910-42A>G		intron	N/A	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.733-42A>G		intron	N/A	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2693 AN: 151714 Hom.: 39 Cov.: 31

Gnomad AFR AF: 0.0130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0457

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0380

Gnomad SAS AF: 0.0301

Gnomad FIN AF: 0.0108

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.0327

GnomAD2 exomes AF: 0.0195 AC: 4908 AN: 251124 AF XY: 0.0193

Gnomad AFR exome AF: 0.0120

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0340

Gnomad FIN exome AF: 0.00972

Gnomad NFE exome AF: 0.0140

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0152 AC: 22045 AN: 1454872 Hom.: 273 Cov.: 30 AF XY: 0.0152 AC XY: 11036 AN XY: 724212

African (AFR) AF: 0.0134 AC: 448 AN: 33332

American (AMR) AF: 0.0368 AC: 1646 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00345 AC: 90 AN: 26062

East Asian (EAS) AF: 0.0433 AC: 1714 AN: 39614

South Asian (SAS) AF: 0.0283 AC: 2436 AN: 86110

European-Finnish (FIN) AF: 0.0103 AC: 547 AN: 53276

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5758

European-Non Finnish (NFE) AF: 0.0127 AC: 14047 AN: 1105882

Other (OTH) AF: 0.0175 AC: 1050 AN: 60156

GnomAD4 genome AF: 0.0178 AC: 2702 AN: 151832 Hom.: 42 Cov.: 31 AF XY: 0.0188 AC XY: 1396 AN XY: 74192

African (AFR) AF: 0.0130 AC: 539 AN: 41388

American (AMR) AF: 0.0457 AC: 696 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3462

East Asian (EAS) AF: 0.0380 AC: 196 AN: 5152

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4816

European-Finnish (FIN) AF: 0.0108 AC: 113 AN: 10500

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.0136 AC: 926 AN: 67986

Other (OTH) AF: 0.0366 AC: 77 AN: 2102

Alfa AF: 0.0125 Hom.: 1

Bravo AF: 0.0193

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.67
PhyloP100		-0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs12491241; hg19: chr3-12558068;