Genetic Variant NM_080701.4:c.446C>T (chrX-153444985-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_080701.4(TREX2):c.446C>T(p.Pro149Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,177,293 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000022 ( 0 hom. 5 hem. )

Consequence

TREX2
NM_080701.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.250

Variant links:

Genes affected

TREX2 (HGNC:12270): (three prime repair exonuclease 2) This gene encodes a nuclear protein with 3' to 5' exonuclease activity. The encoded protein participates in double-stranded DNA break repair, and may interact with DNA polymerase delta. [provided by RefSeq, Nov 2012]

TREX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.066764146).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX2	NM_080701.4 link	c.446C>T	p.Pro149Leu	missense_variant	Exon 2 of 2	ENST00000370231.3	NP_542432.2	Q9BQ50-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREX2	ENST00000370231.3 link	c.446C>T	p.Pro149Leu	missense_variant	Exon 2 of 2	5	NM_080701.4	ENSP00000359251.2		Q9BQ50-2

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112619

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34881

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000285

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

GnomAD3 exomes

AF:

0.0000434

AC:

AN:

115100

Hom.:

AF XY:

0.00

AC XY:

AN XY:

35322

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000104

Gnomad SAS exome

AF:

0.0000715

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000459

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000216

AC:

AN:

1064674

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

344650

show subpopulations

Gnomad4 AFR exome

AF:

0.0000387

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000209

Gnomad4 SAS exome

AF:

0.0000198

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112619

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34881

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000285

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000367

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446C>T (p.P149L) alteration is located in exon 2 (coding exon 1) of the TREX2 gene. This alteration results from a C to T substitution at nucleotide position 446, causing the proline (P) at amino acid position 149 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.7

DANN

Benign

0.87

DEOGEN2

Benign

0.18

.;.;T;.;.;T;T

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.56

T;.;T;.;.;.;.

M_CAP

Benign

0.027

MetaRNN

Benign

0.067

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.36

.;.;N;.;.;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.0

N;N;.;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.80

T;T;.;T;T;T;T

Sift4G

Benign

0.41

T;T;T;T;T;T;T

Polyphen

0.65

.;.;P;.;.;P;P

Vest4

0.11

MutPred

0.41

.;.;Gain of helix (P = 0.0496);.;.;Gain of helix (P = 0.0496);Gain of helix (P = 0.0496);

MVP

0.26

MPC

0.023

ClinPred

0.061

GERP RS

5.0

Varity_R

0.17

gMVP

0.45

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over