chr3-12516464-G-A

Variant names:

• chr3-12516464-G-A
• rs761654828
• NM_025265.4:c.910-147G>A

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.910-147G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 686,162 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (42 hom., cov: 30)
  • Exomes 𝑓: 0.016 (258 hom.)
• Consequence: TSEN2 NM_025265.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.35
• Publications: 0 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=-1.03).
• BP6: Variant 3-12516464-G-A is Benign according to our data. Variant chr3-12516464-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1187150.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 = 0.0154 (2335/151698) while in subpopulation AMR AF = 0.0439 (668/15208). AF 95% confidence interval is 0.0412. There are 42 homozygotes in GnomAd4. There are 1220 alleles in the male GnomAd4 subpopulation. Median coverage is 30. 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.910-147G>A		intron	N/A	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.910-147G>A		intron	N/A	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.910-147G>A		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.910-147G>A		intron	N/A	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.910-147G>A		intron	N/A	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.733-147G>A		intron	N/A	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2328 AN: 151580 Hom.: 40 Cov.: 30

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0439

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0372

Gnomad SAS AF: 0.0297

Gnomad FIN AF: 0.0104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.0293

GnomAD4 exome AF: 0.0162 AC: 8638 AN: 534464 Hom.: 258 AF XY: 0.0162 AC XY: 4668 AN XY: 288136

African (AFR) AF: 0.00438 AC: 67 AN: 15298

American (AMR) AF: 0.0305 AC: 1005 AN: 32934

Ashkenazi Jewish (ASJ) AF: 0.00326 AC: 60 AN: 18408

East Asian (EAS) AF: 0.0430 AC: 1336 AN: 31086

South Asian (SAS) AF: 0.0248 AC: 1474 AN: 59458

European-Finnish (FIN) AF: 0.00989 AC: 362 AN: 36594

Middle Eastern (MID) AF: 0.0131 AC: 33 AN: 2516

European-Non Finnish (NFE) AF: 0.0124 AC: 3836 AN: 308932

Other (OTH) AF: 0.0159 AC: 465 AN: 29238

GnomAD4 genome AF: 0.0154 AC: 2335 AN: 151698 Hom.: 42 Cov.: 30 AF XY: 0.0164 AC XY: 1220 AN XY: 74168

African (AFR) AF: 0.00573 AC: 237 AN: 41364

American (AMR) AF: 0.0439 AC: 668 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3460

East Asian (EAS) AF: 0.0372 AC: 192 AN: 5156

South Asian (SAS) AF: 0.0291 AC: 140 AN: 4808

European-Finnish (FIN) AF: 0.0104 AC: 110 AN: 10556

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 906 AN: 67842

Other (OTH) AF: 0.0328 AC: 69 AN: 2102

Alfa AF: 0.00175 Hom.: 1

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	-1.0
CADD	Benign	0.067
DANN	Benign	0.20
PhyloP100		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism

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: rs761654828; hg19: chr3-12557963;