rs78300695

chr3-48466711-T-TG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_033629.6(TREX1):c.58dup(p.Glu20GlyfsTer82) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: TREX1 NM_033629.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.62

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PP5: Variant 3-48466711-T-TG is Pathogenic according to our data. Variant chr3-48466711-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 126390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TREX1	NM_033629.6	c.58dup	p.Glu20GlyfsTer82	frameshift_variant	2/2	ENST00000625293.3
ATRIP	NM_130384.3	c.*1159dup		3_prime_UTR_variant	13/13	ENST00000320211.10
ATRIP-TREX1	NR_153405.1	n.3367dup		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TREX1	ENST00000625293.3	c.58dup	p.Glu20GlyfsTer82	frameshift_variant	2/2		NM_033629.6	P1
ATRIP	ENST00000320211.10	c.*1159dup		3_prime_UTR_variant	13/13	1	NM_130384.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251392 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000540 AC: 79 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.0000756 AC XY: 55 AN XY: 727220

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: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74434

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 05, 2015	This heterozygous duplication variant is predicted to create a substitution of a glutamic acid to a glycine at position 75 and cause a frameshift and premature truncation 82 amino acids downstream, NP_057465.1(TREX1): p.(Glu75Glyfs*82). This change is predicted to be disease-causing by in-silico models and is novel. It was identified in a patient with clinical features of AGS, and a second truncating mutation in trans. -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Frameshift variant c.26_27insG in Exon 2 of the TREX1 gene that results in the amino acid substitution p.Glu10fs*82 was identified. The observed variant has a minor allele frequency of 0.00013% in gnomAD exomes and novel in gnomAD genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 126390]. The observed variant has been previously reported as a compound heterozygous and a homozygous mutation in patients with Aicardi-Goutieres syndrome (Dillon OJ, et.al., 2018). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Mar 13, 2014	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 02, 2023	The homozygous p.Glu20GlyfsTer82 variant in TREX1 was identified by our study in one individual with Aicardi Goutieres syndrome. The p.Glu20GlyfsTer82 variant in TREX1 has been previously reported in 12 unrelated individuals with Aicardi Goutieres syndrome 1 (PMID: 26938784, PMID: 33235754, PMID: 25604658, PMID: 16845398) but has been identified in 0.1% (32/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs770193197). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 12 previously reported unrelated individuals (PMID: 26938784, PMID: 33235754, PMID: 25604658, PMID: 16845398), 7 were homozygotes (PMID: 16845398, PMID: 25604658), 1 was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 26938784, ClinVar ID: 369666), and 2 were compound heterozygotes who carried pathogenic or likely pathogenic variants in unknown phase (PMID: 33235754, ClinVar Variation ID: 126384, 126392), which increases the likelihood that the p.Glu20GlyfsTer82 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 126390) and has been interpreted as pathogenic by Invitae, Rady Children's Institute for Genomic Medicine, Murdoch Childrens Research Institute Victorian Clinical Genetics Services, GeneReviews, and Sanjay Gandhi Post Graduate Institute of Medical Sciences Department of Medical Genetics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 20 and leads to a premature termination codon 82 amino acids downstream. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TREX1 gene is an established disease mechanism in autosomal recessive Aicardi Goutieres syndrome 1. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Aicardi Goutieres syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong (Richards 2015). -

TREX1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 24, 2023

The TREX1 c.58dupG variant is predicted to result in a frameshift and premature protein termination (p.Glu20Glyfs*82). This variant (aka c.223dup, p.Glu75Glyfs*82) has been reported in the homozygous or compound heterozygous states in multiple individuals with Aicardi-Goutières syndrome (Crow et al. 2006. PubMed ID: 16845398; Crow et al. 2015. PubMed ID: 25604658. Table S1; Lim et al. 2015. PubMed ID: 26182405. Supplementary file 1; Dillon et al. 2018. PubMed ID: 29453417. Table S1). This variant is reported in 0.10% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in TREX1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Dec 25, 2023

- -

Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change creates a premature translational stop signal (p.Glu20Glyfs*82) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 295 amino acid(s) of the TREX1 protein. This variant is present in population databases (rs748398051, gnomAD 0.1%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and neurological features (PMID: 16845398, 25604658). This variant is also known as 58_59insG (E20fs). ClinVar contains an entry for this variant (Variation ID: 126390). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the TREX1 protein in which other variant(s) (p.Arg164*) have been determined to be pathogenic (PMID: 16845398, 25604658). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

TREX1-Related Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Oct 28, 2020

This frameshift variant is found in the only exon of TREX1, and frameshift variants located downstream of this variant have been reported as disease-causing variants in the Human Gene Mutation Database (PMID: 24183309, 20301648). This variant has been previously reported as a compound heterozygous and a homozygous change in patients with Aicardi-Goutieres syndrome (PMID: 16845398, 26182405, 28832562, 29453417). It is present in the heterozygous state in the gnomAD population database at a frequency of .013% (32/251392) and thus is presumed to be rare. Based on the available evidence, the c.28dup (p.Glu10GlyfsTer82) variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs78300695; hg19: chr3-48508110;