Genetic Variant NM_080701.4:c.266G>A (chrX-153445165-C-T) – 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.266G>A(p.Arg89Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,207,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 45 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000097 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.00013 ( 0 hom. 44 hem. )

Consequence

TREX2
NM_080701.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.201

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=0.066743195).

BS2

High Hemizygotes in GnomAdExome4 at 44 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX2	NM_080701.4 link	c.266G>A	p.Arg89Gln	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.266G>A	p.Arg89Gln	missense_variant	Exon 2 of 2	5	NM_080701.4	ENSP00000359251.2		Q9BQ50-2

Frequencies

GnomAD3 genomes

AF:

0.0000971

AC:

AN:

113241

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

35403

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000185

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:

0.000169

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000131

AC:

AN:

168345

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

58039

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000154

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.000241

GnomAD4 exome

AF:

0.000126

AC:

138

AN:

1094568

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

360882

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000665

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000252

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.0000971

AC:

AN:

113241

Hom.:

Cov.:

AF XY:

0.0000282

AC XY:

AN XY:

35403

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000185

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000169

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.266G>A (p.R89Q) alteration is located in exon 2 (coding exon 1) of the TREX2 gene. This alteration results from a G to A substitution at nucleotide position 266, causing the arginine (R) at amino acid position 89 to be replaced by a glutamine (Q). 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

0.075

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.3

DANN

Benign

0.94

DEOGEN2

Benign

0.058

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

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.68

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

M_CAP

Benign

0.016

MetaRNN

Benign

0.067

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;.;L;.;.;L;L

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.47

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

REVEL

Benign

0.10

Sift

Benign

0.35

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

Sift4G

Benign

0.63

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

Polyphen

0.75

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

Vest4

0.11

MVP

0.072

MPC

0.023

ClinPred

0.023

GERP RS

2.8

Varity_R

0.12

gMVP

0.23

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