Genetic Variant NM_080701.4:c.374C>T (chrX-153445057-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_080701.4(TREX2):c.374C>T(p.Pro125Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000884 in 113,072 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. P125R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

TREX2
NM_080701.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.77

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080701.4. 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
	TREX2	NM_080701.4	MANE Select	c.374C>T	p.Pro125Leu	missense	Exon 2 of 2	NP_542432.2	Q9BQ50-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TREX2	ENST00000370231.3	TSL:5 MANE Select	c.374C>T	p.Pro125Leu	missense	Exon 2 of 2	ENSP00000359251.2	Q9BQ50-2
TREX2	ENST00000334497.7	TSL:1	c.503C>T	p.Pro168Leu	missense	Exon 11 of 11	ENSP00000334993.2	Q9BQ50-1
TREX2	ENST00000370232.4	TSL:1	c.503C>T	p.Pro168Leu	missense	Exon 11 of 11	ENSP00000359252.1	Q9BQ50-1

Frequencies

GnomAD3 genomes

AF:

0.00000884

AC:

AN:

113072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000321

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

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1055663

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

337429

African (AFR)

AF:

0.00

AC:

AN:

25519

American (AMR)

AF:

0.00

AC:

AN:

29453

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17504

East Asian (EAS)

AF:

0.00

AC:

AN:

28664

South Asian (SAS)

AF:

0.00

AC:

AN:

48453

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4018

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

820783

Other (OTH)

AF:

0.00

AC:

AN:

44191

GnomAD4 genome

AF:

0.00000884

AC:

AN:

113072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35228

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31175

American (AMR)

AF:

0.00

AC:

AN:

10871

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2661

East Asian (EAS)

AF:

0.00

AC:

AN:

3560

South Asian (SAS)

AF:

0.00

AC:

AN:

2828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6299

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53231

Other (OTH)

AF:

0.00

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.54

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.7

PhyloP100

3.8

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-8.7

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.71

MutPred

0.69

Loss of helix (P = 0.1299)

MVP

0.81

MPC

0.19

ClinPred

1.0

GERP RS

5.0

Varity_R

0.81

gMVP

0.68

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over