rs72556554

Positions:

• chr3-48466996-G-A
• chr3-48466996-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM5 PP3 PP5

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:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21 B:2 O:1
• Conservation: PhyloP100: 4.73

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]

ATRIP-TREX1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48466996-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2665003.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 3-48466996-G-A is Pathogenic according to our data. Variant chr3-48466996-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4179.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=14, Benign=1, Likely_pathogenic=1}. Variant chr3-48466996-G-A is described in Lovd as [Pathogenic]. Variant chr3-48466996-G-A is described in Lovd as [Likely_pathogenic].

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: 46 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000208 AC: 52 AN: 249654 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135264

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.000502 AC XY: 365 AN XY: 726832

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000656

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74316

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000600

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:21 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Pathogenic	0.92	D
MutationTaster	Benign	0.99	A;A;A;A;A;A
PrimateAI	Uncertain	0.51	T
Vest4		0.80
MVP		0.91
ClinPred		0.52	D
GERP RS		5.0
Varity_R		0.50
gMVP		0.48

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: rs72556554; hg19: chr3-48508395;