chrX-153444985-G-A

Variant names:

• chrX-153444985-G-A
• rs781837494
• NM_080701.4:c.446C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 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. P149S) has been classified 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.250
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.066764146).
• BS2: High Hemizygotes in GnomAdExome4 at 5 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.446C>T	p.Pro149Leu	missense	Exon 2 of 2	NP_542432.2	Q9BQ50-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX2	ENST00000370231.3	TSL:5 MANE Select	c.446C>T	p.Pro149Leu	missense	Exon 2 of 2	ENSP00000359251.2	Q9BQ50-2
	TREX2	ENST00000334497.7	TSL:1	c.575C>T	p.Pro192Leu	missense	Exon 11 of 11	ENSP00000334993.2	Q9BQ50-1
	TREX2	ENST00000370232.4	TSL:1	c.575C>T	p.Pro192Leu	missense	Exon 11 of 11	ENSP00000359252.1	Q9BQ50-1

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112619 Hom.: 0 Cov.: 25

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

GnomAD2 exomes AF: 0.0000434 AC: 5 AN: 115100 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000459

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000216 AC: 23 AN: 1064674 Hom.: 0 Cov.: 31 AF XY: 0.0000145 AC XY: 5 AN XY: 344650

African (AFR) AF: 0.0000387 AC: 1 AN: 25822

American (AMR) AF: 0.00 AC: 0 AN: 29741

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18526

East Asian (EAS) AF: 0.000209 AC: 6 AN: 28735

South Asian (SAS) AF: 0.0000198 AC: 1 AN: 50561

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3986

European-Non Finnish (NFE) AF: 0.0000182 AC: 15 AN: 825462

Other (OTH) AF: 0.00 AC: 0 AN: 44762

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112619 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 34881

African (AFR) AF: 0.00 AC: 0 AN: 31036

American (AMR) AF: 0.00 AC: 0 AN: 10816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3503

South Asian (SAS) AF: 0.00 AC: 0 AN: 2811

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6275

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53080

Other (OTH) AF: 0.00 AC: 0 AN: 1536

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000367 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.7
DANN	Benign	0.87
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.36	N
PhyloP100		0.25
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.80	T
Sift4G	Benign	0.41	T
Polyphen		0.65	P
Vest4		0.11
MutPred		0.41		Gain of helix (P = 0.0496)
MVP		0.26
MPC		0.023
ClinPred		0.061	T
GERP RS		5.0
Varity_R		0.17
gMVP		0.45
Mutation Taster		=88/12	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: rs781837494; hg19: chrX-152710443;