rs78218009

Positions:

chr3-48467145-C-T

Variant summary

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

The NM_033629.6(TREX1):c.490C>T(p.Arg164Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,900 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

TREX1
NM_033629.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 0.553

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 13 pathogenic variants in the truncated region.

PP5

Variant 3-48467145-C-T is Pathogenic according to our data. Variant chr3-48467145-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48467145-C-T is described in Lovd as [Pathogenic]. Variant chr3-48467145-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TREX1	NM_033629.6 linkuse as main transcript	c.490C>T	p.Arg164Ter	stop_gained	2/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3 linkuse as main transcript	c.*1591C>T		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1
ATRIP-TREX1	NR_153405.1 linkuse as main transcript	n.3799C>T		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3 linkuse as main transcript	c.490C>T	p.Arg164Ter	stop_gained	2/2		NM_033629.6	ENSP00000486676	P1	Q9NSU2-3
ATRIP	ENST00000320211.10 linkuse as main transcript	c.*1591C>T		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099	P1	Q8WXE1-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Aicardi-Goutieres syndrome 1

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2006	- -

TREX1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

The TREX1 c.655C>T variant is predicted to result in premature protein termination (p.Arg219*). This variant was reported in the homozygous state in patients with Aicardi-Goutières syndrome and it is found to be a recurrent founder mutation in TREX1 observed in individuals of Cree ancestry (reported as c.490C>T, p.Arg164* in Crow YJ et al 2006. PubMed ID: 16845398; Crow YJ et al 1993. PubMed ID: 20301648; supple Table 1 in Crow YJ et al 2015. PubMed ID: 25604658). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in TREX1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 23, 2018

The R164X variant in the TREX1 gene has been reported previously in the homozygousstate in an individual with Aicardi-Goutieres syndrome; this individual's consanguineous unaffected parents were both found to be heterozygous carriers of the variant (Crow et al., 2006). This variant is predicted to cause loss of normal protein function through protein truncation. The R164X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R164X as a likely pathogenic variant. -

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change creates a premature translational stop signal (p.Arg164*) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 151 amino acid(s) of the TREX1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal recessive Aicardi-Goutieres syndrome (PMID: 16845398, 25604658; Invitae). It is commonly reported in individuals of Cree Native American ancestry (PMID: 25604658). ClinVar contains an entry for this variant (Variation ID: 4180). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.10

MutationTaster

Benign

1.0

A;A;A;A;A;A

Vest4

0.82

GERP RS

3.0

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

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