chrX-153445057-G-C

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_080701.4(TREX2):​c.374C>G​(p.Pro125Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000853 in 1,055,663 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000085 (0 hom. 3 hem.)
• Consequence: TREX2 NM_080701.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX2	NM_080701.4	c.374C>G	p.Pro125Arg	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>G	p.Pro125Arg	missense_variant	Exon 2 of 2	5	NM_080701.4	ENSP00000359251.2

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000272 AC: 3 AN: 110147 Hom.: 0 AF XY: 0.0000760 AC XY: 2 AN XY: 26325

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000306

Gnomad SAS 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: 0.00000853 AC: 9 AN: 1055663 Hom.: 0 Cov.: 31 AF XY: 0.00000889 AC XY: 3 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: 0.000244

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000244

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000227

ExAC AF: 0.0000173 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374C>G (p.P125R) alteration is located in exon 2 (coding exon 1) of the TREX2 gene. This alteration results from a C to G substitution at nucleotide position 374, causing the proline (P) at amino acid position 125 to be replaced by an arginine (R). 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	Uncertain	0.54
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;.;D;.;.;D;D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;.;T;.;.;.;.
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.7	.;.;L;.;.;L;L
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.8	D;D;.;D;D;D;D
REVEL	Uncertain	0.48
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		0.78
MutPred		0.73		.;.;Gain of methylation at P168 (P = 0.0392);.;.;Gain of methylation at P168 (P = 0.0392);Gain of methylation at P168 (P = 0.0392);
MVP		0.75
MPC		0.19
ClinPred		0.66	D
GERP RS		5.0
Varity_R		0.89
gMVP		0.66

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;