3-12519111-C-T

Variant names:

• chr3-12519111-C-T
• rs145142315
• NM_025265.4:c.1013C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_025265.4(TSEN2):​c.1013C>T​(p.Thr338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T338R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TSEN2 NM_025265.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3835098).

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.1013C>T	p.Thr338Met	missense	Exon 8 of 12	NP_079541.1	Q8NCE0-1
	TSEN2	NM_001321278.2		c.1013C>T	p.Thr338Met	missense	Exon 8 of 12	NP_001308207.1	C9J7Z4
	TSEN2	NM_001145392.2		c.1013C>T	p.Thr338Met	missense	Exon 8 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.1013C>T	p.Thr338Met	missense	Exon 8 of 12	ENSP00000284995.6	Q8NCE0-1
	TSEN2	ENST00000402228.7	TSL:1	c.1013C>T	p.Thr338Met	missense	Exon 8 of 12	ENSP00000385976.3	Q8NCE0-1
	TSEN2	ENST00000454502.6	TSL:1	c.836C>T	p.Thr279Met	missense	Exon 9 of 13	ENSP00000392029.2	Q8NCE0-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251486 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.5
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.39		Gain of MoRF binding (P = 0.0772)
MVP		0.67
MPC		0.14
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.10
gMVP		0.40
Mutation Taster		=97/3	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: rs145142315; hg19: chr3-12560610; COSMIC: COSV53191112; COSMIC: COSV53191112;