3-48466860-CTG-CTGTG

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_033629.6(TREX1):c.212_213dupTG(p.Ala72TrpfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000684 in 1,461,448 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A72A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TREX1
NM_033629.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2O:1

Conservation

PhyloP100: 3.68

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: MODERATE Submitted by: G2P
Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ATRIP links:

ATRIP-TREX1 (HGNC:):

ATRIP-TREX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 62 pathogenic variants in the truncated region.

PP5

Variant 3-48466860-C-CTG is Pathogenic according to our data. Variant chr3-48466860-C-CTG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033629.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TREX1	NM_033629.6	MANE Select	c.212_213dupTG	p.Ala72TrpfsTer17	frameshift	Exon 2 of 2	NP_338599.1
ATRIP	NM_130384.3	MANE Select	c.1313_1314dupTG		3_prime_UTR	Exon 13 of 13	NP_569055.1
TREX1	NM_007248.5		c.182_183dupTG	p.Ala62TrpfsTer17	frameshift	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TREX1	ENST00000625293.3	TSL:6 MANE Select	c.212_213dupTG	p.Ala72TrpfsTer17	frameshift	Exon 2 of 2	ENSP00000486676.2
TREX1	ENST00000444177.1	TSL:1	c.182_183dupTG	p.Ala62TrpfsTer17	frameshift	Exon 2 of 2	ENSP00000415972.1
TREX1	ENST00000433541.1	TSL:1	c.-206_-205dupTG		5_prime_UTR	Exon 4 of 4	ENSP00000412404.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250946

AF XY:

0.0000221

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461448

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Dec 17, 2019

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Pathogenic:1

Dec 13, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ala72Trpfs*17) in the TREX1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 243 amino acid(s) of the TREX1 protein. This variant is present in population databases (rs775500897, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 17846997). This variant disrupts the C-terminus of the TREX1 protein. Other variant(s) that disrupt this region (p.I156Tfs*4, p.T157Mfs*3, p.Trp210*) have been observed in individuals with TREX1-related conditions (PMID: 16845398, 24183309, 25604658, 26938784). This suggests that this may be a clinically significant region of the protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Aicardi-Goutieres syndrome 1

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over