rs72556554
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5PP3PP5
The NM_033629.6(TREX1):c.341G>A(p.Arg114His) variant causes a missense change. The variant allele was found at a frequency of 0.00051 in 1,613,086 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_033629.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TREX1 | NM_033629.6 | c.341G>A | p.Arg114His | missense_variant | 2/2 | ENST00000625293.3 | |
ATRIP | NM_130384.3 | c.*1442G>A | 3_prime_UTR_variant | 13/13 | ENST00000320211.10 | ||
ATRIP-TREX1 | NR_153405.1 | n.3650G>A | non_coding_transcript_exon_variant | 15/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TREX1 | ENST00000625293.3 | c.341G>A | p.Arg114His | missense_variant | 2/2 | NM_033629.6 | P1 | ||
ATRIP | ENST00000320211.10 | c.*1442G>A | 3_prime_UTR_variant | 13/13 | 1 | NM_130384.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000302 AC: 46AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000208 AC: 52AN: 249654Hom.: 0 AF XY: 0.000185 AC XY: 25AN XY: 135264
GnomAD4 exome AF: 0.000531 AC: 776AN: 1460932Hom.: 0 Cov.: 31 AF XY: 0.000502 AC XY: 365AN XY: 726832
GnomAD4 genome ? AF: 0.000302 AC: 46AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:9
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | TREX1: PM3:Very Strong, PM5, PM2:Supporting, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 04, 2018 | The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease. However, available data lack unaffected family members. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2022 | Published functional studies demonstrate the mutant homozygous and compound heterozygous R114H protein has dysfunctional exonuclease activity when compared to the wild type protein (de Silva et al., 2007; Orebaugh et al., 2011; Lehtinen et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17293595, 18805785, 18045533, 16845398, 23881107, 27391121, 26182405, 28089741, 29239743, 17660818, 17846997, 20131292, 31980526, 34426522, 30219631, 33504652, 21937424, 21270825) - |
Aicardi-Goutieres syndrome 1 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 10, 2015 | The p.Arg114His variant in TREX1 has been reported in at least 23 homozygous and 11 compound heterozygous individuals with Aicardi-Goutieres syndrome (Crow 2006, Crow 2015). This variant has been identified in 0.06% (5/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72556554). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro studies suggest that the p.Arg114His variant may lead to a reduction in TREX1 endonuclease activity (de Silva 2007 Lehtinen 2008); however, these types of assays may not accurately reflect biological function. In summary, this variant meets our criteria to be classified as pathogenic for Aicardi-Goutieres syndrome in an autosomal recessive manner. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2007 | - - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Mar 13, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 18, 2023 | Variant summary: TREX1 c.341G>A (p.Arg114His) results in a non-conservative amino acid change located in the Exonuclease, RNase T/DNA polymerase III (IPR013520) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 249654 control chromosomes. c.341G>A has been reported in the literature in multiple individuals affected with Aicardi Goutieres Syndrome 1 (example: Rice_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Lehtinen_2008). The following publications have been ascertained in the context of this evaluation (PMID: 18805785, 17846997). 15 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as pathogenic (n=10), likely pathogenic (n=1), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The TREX1 c.341G>A (p.Arg114His) missense variant, also referred to as c.506G>A (p.Arg169His), has been identified in 25 individuals with Aicardi-Goutieres syndrome, including in a homozygous state in 20 individuals and in a compound heterozygous state in five individuals (Crow et al. 2006; Rice et al. 2007). Control data are unavailable for this variant, which is reported at a frequency of 0.00068 in the African-American population of the Exome Sequencing Project. Expression analysis revealed no detectable TREX1 activity in any of the individuals with p.Arg114His (Crow et al. 2006). A study by Orebaugh et al. (2011) found that compound heterozygous individuals for the p.Arg114His variant and the p.Asp201ins variant displayed reduced enzyme activity, but activity was not as diminished as in those homozygous for the p.Arg114His variant. The same study also implicated heterozygous TREX1 variants (in particular p.Arg114His) as a risk allele for systemic lupus erythematosus, which was confirmed by Lehtinen et al. (2008). Based on the collective evidence, the p.Arg114His variant is classified as pathogenic for Aicardi-Goutieres syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 09, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Jul 10, 2015 | The c.341G>A (p.Arg114His) missense variant in the TREX1 gene has been previously reported in affected individuals and is known to represent ~50% of the AGS-associated genotypes (Orebaugh et al. 2011). This variant results in a 50-fold reduction in enzyme activity and is localized to the dimer interface of the protein and is important for dimer stabilization (de Silva et al. 2007). This p.Arg114His variant has been reported at very low frequency in the control population databases (Exome Sequencing Project [ESP], and ExAc, and not reported in 1000 Genomes) and has been predicted as deleterious by computational algorithms. In addition, it has been described as pathogenic in ClinVar (OMIM and GeneReviews). Therefore, this collective evidence supports the classification of the c.341G>A (p.Arg114His) as a heterozygous pathogenic variant for Aicardi-Goutieres syndrome 1. - |
Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 114 of the TREX1 protein (p.Arg114His). This variant is present in population databases (rs72556554, gnomAD 0.04%). This missense change has been observed in individuals with Aicardi-Goutieres syndrome (PMID: 16845398, 28089741). ClinVar contains an entry for this variant (Variation ID: 4179). 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. Experimental studies have shown that this missense change affects TREX1 function (PMID: 16845398, 17293595, 18805785). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 31, 2017 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2018 | - - |
TREX1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 09, 2023 | The TREX1 c.341G>A variant is predicted to result in the amino acid substitution p.Arg114His. This variant is also reported as c.341G>A, p.Arg114His in an alternative transcript (NM_ 033629.4). This variant has been reported in the compound heterozygous and homozygous state in many individuals with Aicardi-Goutieres syndrome (Crow et al. 2006. PubMed ID: 16845398; Rice et al. 2007. PubMed ID: 17846997; Tumienė et al. 2017. PubMed ID: 28089741; Crow et al. 2015. PubMed ID: 25604658). The c.506G>A variant is the most common recessive, pathogenic TREX1 variant and has been functionally characterized to have reduced enzyme activity (Crow et al. 2015. PubMed ID: 25604658; Orebaugh et al. 2011. PubMed ID: 21937424). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-48508395-G-A). In summary, the c.506G>A variant is pathogenic for autosomal recessive TREX1-related disorders. - |
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. - |
Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C0950123:Inborn genetic diseases Benign:1
Likely benign, no assertion criteria provided | research | Institute of Neurology, Charite University of Medicine | Jun 04, 2022 | - - |
Systemic lupus erythematosus, susceptibility to Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Oct 01, 2007 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at