chr3-48467513-GCTGCTGGCCCCACTGGGT-G

Position:

• chr3-48467513-GCTGCTGGCCCCACTGGGT-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM4 PP5_Very_Strong

The NM_033629.6(TREX1):​c.868_885del​(p.Pro290_Ala295del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000088 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (0 hom.)
• Consequence: TREX1 NM_033629.6 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 3.94

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 10 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_033629.6.
• PP5: Variant 3-48467513-GCTGCTGGCCCCACTGGGT-G is Pathogenic according to our data. Variant chr3-48467513-GCTGCTGGCCCCACTGGGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 126393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48467513-GCTGCTGGCCCCACTGGGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREX1	NM_033629.6	c.868_885del	p.Pro290_Ala295del	inframe_deletion	2/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*1969_*1986del		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1
ATRIP-TREX1	NR_153405.1	n.4177_4194del		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3	c.868_885del	p.Pro290_Ala295del	inframe_deletion	2/2		NM_033629.6	ENSP00000486676	P1
ATRIP	ENST00000320211.10	c.*1969_*1986del		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251074 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135790

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000910 AC: 133 AN: 1461712 Hom.: 0 AF XY: 0.0000853 AC XY: 62 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000854

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 1 Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000126393 / PMID: 17846997). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2023	Variant summary: TREX1 c.868_885del18 (p.Pro290_Ala295del), also referred to as c.859_876del18 (p.Leu287_Gly292del), results in an in-frame deletion that is predicted to remove six amino acids from the encoded protein. The variant allele was found at a frequency of 6.4e-05 in 251074 control chromosomes (gnomAD). c.868_885del18 has been reported in the literature in multiple individuals affected with Aicardi Goutieres Syndrome 1, including homozygous patients from at least three different families (e.g. Rice_2007, Ramantani_2010, Abe_2014, Crow_2015). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24300241, 25604658, 20131292, 17846997). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as either pathogenic (n=2) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	TREX1: PM3:Strong, PM2, PM4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 07, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2023	In-frame deletion of six amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20301648, 17846997, 25582466, 20131292, 28750028, 31719132, 29387804, 31130681, 24300241, 27943079, 35551623, 34426522, 33683010, 37081257) -

Aicardi Goutieres syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Pediatrics, Sichuan Provincial Hospital For Women And Children

-

The proband, male, 3 months old, was found to have widened lateral ventricles during the fetal period, had feeding difficulties after birth, did not gain weight, and was found to have microcephaly and nystagmus by physical examination. MRI revealed calcification in the skull, thrombocytopenia in blood routine, and elevated aminotransferase in liver function. During the follow-up observation period of more than 1 year, the patient developed recurrent chilblains and pneumonia and global development delay. -

TREX1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

The TREX1 c.868_885del18 variant is predicted to result in an in-frame deletion (p.Pro290_Ala295del). This variant has been reported as causative in several patients with autosomal recessive Aicardi-Goutières syndrome (described as p.Pro290_Ala295del, Abe et al. 2014. PubMed ID: 24300241; Rice et al. 2007. PubMed ID: 17846997; Tise et al. 2021. PubMed ID: 33683010). This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Breakthrough Genomics, Breakthrough Genomics

Oct 23, 2019

This variant (represented as c.868_885del/c.859_876del in articles) was previously reported as pathogenic in homozygous state or compound heterozygous state in patients affected with AGS [PMID: 17846997, 20131292, 24300241, 28750028]. Heterozygous TREX1 mutations were described in a cutaneous form of SLE-called FCL [PMID:17440703] and in patients with an adult-onset RVCL [PMID: 16960810]. In addition, heterozygous TREX1 mutations were found in individuals with SLE [PMID:17660818]. -

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

Dec 22, 2023

This variant, c.868_885del, results in the deletion of 6 amino acid(s) of the TREX1 protein (p.Pro290_Ala295del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs776342560, gnomAD 0.03%). This variant has been observed in individual(s) with Aicardi Goutieres syndrome (PMID: 20131292, 24300241, 25582466, 28750028). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.859_876del18; p.Leu287_Gly292del. ClinVar contains an entry for this variant (Variation ID: 126393). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs79318303; hg19: chr3-48508912;