rs755919767
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The ENST00000433541(TREX1):c.-200C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000155 in 1,613,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
TREX1
ENST00000433541 5_prime_UTR_premature_start_codon_gain
ENST00000433541 5_prime_UTR_premature_start_codon_gain
Scores
10
4
3
Clinical Significance
Conservation
PhyloP100: 4.97
Genes affected
TREX1 (HGNC:12269): (three prime repair exonuclease 1) This gene encodes a nuclear protein with 3' exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]
ATRIP (HGNC:33499): (ATR interacting protein) This gene encodes an essential component of the DNA damage checkpoint. The encoded protein binds to single-stranded DNA coated with replication protein A. The protein also interacts with the ataxia telangiectasia and Rad3 related protein kinase, resulting in its accumulation at intranuclear foci induced by DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.971
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TREX1 | NM_033629.6 | c.218C>T | p.Pro73Leu | missense_variant | Exon 2 of 2 | ENST00000625293.3 | NP_338599.1 | |
ATRIP | NM_130384.3 | c.*1319C>T | 3_prime_UTR_variant | Exon 13 of 13 | ENST00000320211.10 | NP_569055.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TREX1 | ENST00000625293.3 | c.218C>T | p.Pro73Leu | missense_variant | Exon 2 of 2 | 6 | NM_033629.6 | ENSP00000486676.2 | ||
ATRIP | ENST00000320211.10 | c.*1319C>T | 3_prime_UTR_variant | Exon 13 of 13 | 1 | NM_130384.3 | ENSP00000323099.3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250524Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135524
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461098Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 726896
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2024 | TREX1: PM2, PM3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2024 | Reported in two patients with atypical cerebral palsy and one patient with thrombocytopenia, glaucoma, nystagmus an increased CSF interferon alpha (PMID: 34440436, 34540776); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34540776, 34440436) - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes | Sep 26, 2016 | - - |
Aicardi-Goutieres syndrome 1 Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence, | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 18, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jun 18, 2019 | This TREX1 variant (rs755919767) is rare (<0.1%) in large population datasets (gnomAD: 6/250524 total alleles; 0.0024%; no homozygotes) and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Two submitters classified it as a variant of uncertain clinical significance and one as pathogenic. Two bioinformatic tools queried predict that this substitution would be probably damaging/deleterious, and the proline residue at this position is evolutionarily conserved in mammals. This variant is considered to be likely pathogenic. - |
Systemic lupus erythematosus;C0024145:Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 30, 2025 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 73 of the TREX1 protein (p.Pro73Leu). This variant is present in population databases (rs755919767, gnomAD 0.01%). This missense change has been observed in individual(s) with increased CSF interferon alpha (PMID: 34440436, 34540776, 37597066). ClinVar contains an entry for this variant (Variation ID: 522920). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D
REVEL
Pathogenic
Sift
Pathogenic
.;D
Sift4G
Pathogenic
.;D
Vest4
0.80
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at