chrX-153445057-G-A

Variant names:

• chrX-153445057-G-A
• rs781868111
• NM_080701.4:c.374C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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.

• 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX2	NM_080701.4	c.374C>T	p.Pro125Leu	missense_variant	Exon 2 of 2	ENST00000370231.3	NP_542432.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREX2	ENST00000370231.3	c.374C>T	p.Pro125Leu	missense_variant	Exon 2 of 2	5	NM_080701.4	ENSP00000359251.2

Frequencies

GnomAD3 genomes AF: 0.00000884 AC: 1 AN: 113072 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35228

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: 0 AN: 1055663 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 337429

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000884 AC: 1 AN: 113072 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35228

Gnomad4 AFR AF: 0.0000321

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	.;.;D;.;.;D;D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;.;T;.;.;.;.
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	.;.;M;.;.;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.7	D;D;.;D;D;D;D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;.;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;D;D
Vest4		0.71
MutPred		0.69		.;.;Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.81
MPC		0.19
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.81
gMVP		0.68

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

Other links and lift over

dbSNP: rs781868111; hg19: chrX-152710515;