rs77899976

Variant names:

• chr3-12503280-G-A
• rs77899976
• NM_025265.4:c.327G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-12503280-G-A
• chr3-12503280-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.327G>A​(p.Glu109Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,614,160 control chromosomes in the GnomAD database, including 503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (66 hom., cov: 32)
  • Exomes 𝑓: 0.017 (437 hom.)
• Consequence: TSEN2 NM_025265.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.600
• Publications: 7 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=-0.87).
• BP6: Variant 3-12503280-G-A is Benign according to our data. Variant chr3-12503280-G-A is described in ClinVar as Benign. ClinVar VariationId is 137749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0538 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.327G>A	p.Glu109Glu	synonymous	Exon 5 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.327G>A	p.Glu109Glu	synonymous	Exon 5 of 12	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.327G>A	p.Glu109Glu	synonymous	Exon 5 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.327G>A	p.Glu109Glu	synonymous	Exon 5 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.327G>A	p.Glu109Glu	synonymous	Exon 5 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.327G>A	p.Glu109Glu	synonymous	Exon 5 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3728 AN: 152176 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0472

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.0600

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0364

GnomAD2 exomes AF: 0.0245 AC: 6152 AN: 250798 AF XY: 0.0249

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.0359

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.0338

Gnomad FIN exome AF: 0.00970

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0175 AC: 25532 AN: 1461866 Hom.: 437 Cov.: 31 AF XY: 0.0182 AC XY: 13223 AN XY: 727236

African (AFR) AF: 0.0314 AC: 1050 AN: 33480

American (AMR) AF: 0.0388 AC: 1735 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00344 AC: 90 AN: 26136

East Asian (EAS) AF: 0.0436 AC: 1729 AN: 39700

South Asian (SAS) AF: 0.0554 AC: 4775 AN: 86256

European-Finnish (FIN) AF: 0.0102 AC: 547 AN: 53420

Middle Eastern (MID) AF: 0.0127 AC: 73 AN: 5766

European-Non Finnish (NFE) AF: 0.0129 AC: 14327 AN: 1111992

Other (OTH) AF: 0.0200 AC: 1206 AN: 60392

GnomAD4 genome AF: 0.0245 AC: 3738 AN: 152294 Hom.: 66 Cov.: 32 AF XY: 0.0261 AC XY: 1943 AN XY: 74470

African (AFR) AF: 0.0333 AC: 1385 AN: 41556

American (AMR) AF: 0.0472 AC: 722 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.0378 AC: 196 AN: 5184

South Asian (SAS) AF: 0.0594 AC: 287 AN: 4830

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

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 934 AN: 68030

Other (OTH) AF: 0.0394 AC: 83 AN: 2108

Alfa AF: 0.0168 Hom.: 103

Bravo AF: 0.0258

Asia WGS AF: 0.0910 AC: 316 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0158

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	-0.87
CADD	Benign	0.14
DANN	Benign	0.79
PhyloP100		-0.60
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)		0.0		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: rs77899976; hg19: chr3-12544779; COSMIC: COSV53191635; COSMIC: COSV53191635;