3-48466792-GCCC-GCCCC

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_033629.6(TREX1):c.144dupC(p.Thr49HisfsTer53) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

TREX1
NM_033629.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.334

Variant links:

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]

TREX1 links:

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 links:

ATRIP-TREX1 (HGNC:):

ATRIP-TREX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 16 pathogenic variants in the truncated region.

PP5

Variant 3-48466792-G-GC is Pathogenic according to our data. Variant chr3-48466792-G-GC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 282766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX1	NM_033629.6 link	c.144dupC	p.Thr49HisfsTer53	frameshift_variant	Exon 2 of 2	ENST00000625293.3	NP_338599.1	Q9NSU2-3
ATRIP	NM_130384.3 link	c.*1245dupC		3_prime_UTR_variant	Exon 13 of 13	ENST00000320211.10	NP_569055.1	Q8WXE1-1A0A024R2U4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3 link	c.144dupC	p.Thr49HisfsTer53	frameshift_variant	Exon 2 of 2	6	NM_033629.6	ENSP00000486676.2		Q9NSU2-3
ATRIP	ENST00000320211.10 link	c.*1245dupC		3_prime_UTR_variant	Exon 13 of 13	1	NM_130384.3	ENSP00000323099.3		Q8WXE1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461564

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000170

Gnomad4 NFE exome

AF:

0.0000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152034

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 14, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2021

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 15, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 266 amino acids are replaced with 52 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25604658, 33996686, 33763395, 32860008, 27943079) -

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aicardi-Goutieres syndrome 1

Pathogenic:3

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The homozygous p.Thr49HisfsTer53 variant in TREX1 was identified by our study in one individual with Aicardi Goutieres syndrome. The p.Thr49HisfsTer53 variant in TREX1 has been previously reported in 4 unrelated individuals with Aicardi Goutieres syndrome 1 (PMID: 25604658, PMID: 33099809, PMID: 32860008) but has been identified in 0.007% (1/15274) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs748914604). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 4 previously reported unrelated individuals (PMID: 25604658, PMID: 33099809, PMID: 32860008), 2 were homozygotes, which increases the likelihood that the p.Thr49HisfsTer53 variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 282766) and has been interpreted as pathogenic or likely pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein‚Äôs amino acid sequence beginning at position 49 and leads to a premature termination codon 53 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Aicardi Goutieres syndrome 1. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015). -

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Systemic lupus erythematosus;C0024145:Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations

Pathogenic:1

Feb 07, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TREX1-related disorder

Pathogenic:1

Jan 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TREX1 c.144dupC variant is predicted to result in a frameshift and premature protein termination (p.Thr49Hisfs*53). This variant has been reported in the homozygous state or with a second TREX1 variant in individuals with Aicardi-Goutières syndrome (see, for example, Crow et al 2015. PubMed ID: 25604658; Table S3, Rice et al. 2016. PubMed ID: 27943079; described as c.137_138insC, Wu et al. 2021. PubMed ID: 33996686). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD; however, the quality of this data is questionable and should be treated with caution. Frameshift variants in TREX1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Apr 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr49Hisfs*53) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 266 amino acid(s) of the TREX1 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive Aicardi-Goutieres syndrome (PMID: 25604658). ClinVar contains an entry for this variant (Variation ID: 282766). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over