Genetic Variant TREX2:p.Pro149Ser (chrX-153444986-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_080701.4(TREX2):c.445C>T(p.Pro149Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000034 in 1,177,440 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P149L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000029 ( 0 hom. 14 hem. )

Consequence

TREX2
NM_080701.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.118541926).

BS2

High Hemizygotes in GnomAdExome4 at 14 gene

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.445C>T	p.Pro149Ser	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.445C>T	p.Pro149Ser	missense	Exon 2 of 2	ENSP00000359251.2	Q9BQ50-2
TREX2	ENST00000334497.7	TSL:1	c.574C>T	p.Pro192Ser	missense	Exon 11 of 11	ENSP00000334993.2	Q9BQ50-1
TREX2	ENST00000370232.4	TSL:1	c.574C>T	p.Pro192Ser	missense	Exon 11 of 11	ENSP00000359252.1	Q9BQ50-1

Frequencies

GnomAD3 genomes

AF:

0.0000798

AC:

AN:

112800

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

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:

0.00000869

AC:

AN:

115013

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000148

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000291

AC:

AN:

1064640

Hom.:

Cov.:

AF XY:

0.0000406

AC XY:

AN XY:

344656

show subpopulations

African (AFR)

AF:

0.000774

AC:

AN:

25834

American (AMR)

AF:

0.00

AC:

AN:

29741

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18531

East Asian (EAS)

AF:

0.00

AC:

AN:

28743

South Asian (SAS)

AF:

0.00

AC:

AN:

50552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37051

Middle Eastern (MID)

AF:

0.000251

AC:

AN:

3979

European-Non Finnish (NFE)

AF:

0.00000242

AC:

AN:

825457

Other (OTH)

AF:

0.000179

AC:

AN:

44752

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000798

AC:

AN:

112800

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35014

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

31077

American (AMR)

AF:

0.00

AC:

AN:

10838

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3528

South Asian (SAS)

AF:

0.00

AC:

AN:

2815

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6291

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53151

Other (OTH)

AF:

0.00

AC:

AN:

1534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.0000184

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.081

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.66

M_CAP

Benign

0.015

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

1.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.68

REVEL

Benign

0.11

Sift

Benign

0.61

Sift4G

Benign

0.77

Polyphen

0.94

Vest4

0.37

MutPred

0.34

Gain of helix (P = 0.0496)

MVP

0.14

MPC

0.023

ClinPred

0.099

GERP RS

4.1

Varity_R

0.13

gMVP

0.36

Mutation Taster

=93/7

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over