rs55999987

Variant names:

• chr3-48467452-A-G
• rs55999987
• NM_033629.6:c.797A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033629.6(TREX1):​c.797A>G​(p.Glu266Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,614,140 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (9 hom.)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: -0.429

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004069388).
• BP6: Variant 3-48467452-A-G is Benign according to our data. Variant chr3-48467452-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96242.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=6}. Variant chr3-48467452-A-G is described in Lovd as [Likely_benign]. Variant chr3-48467452-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00175 (266/152278) while in subpopulation NFE AF= 0.00306 (208/68006). AF 95% confidence interval is 0.00272. There are 0 homozygotes in gnomad4. There are 111 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TREX1	NM_033629.6	c.797A>G	p.Glu266Gly	missense_variant	Exon 2 of 2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*1898A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000320211.10	NP_569055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3	c.797A>G	p.Glu266Gly	missense_variant	Exon 2 of 2	6	NM_033629.6	ENSP00000486676.2
ATRIP	ENST00000320211.10	c.*1898A>G		3_prime_UTR_variant	Exon 13 of 13	1	NM_130384.3	ENSP00000323099.3

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00306

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00165 AC: 416 AN: 251436 Hom.: 1 AF XY: 0.00168 AC XY: 229 AN XY: 135912

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00314 AC: 4591 AN: 1461862 Hom.: 9 Cov.: 33 AF XY: 0.00310 AC XY: 2255 AN XY: 727240

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.00384

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.00149 AC XY: 111 AN XY: 74468

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00306

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00279 Hom.: 2

Bravo AF: 0.00182

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00169 AC: 205

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TREX1: BP4, BS2 -

Sep 24, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 23, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:3 Benign:1

Dec 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TREX1 c.797A>G (p.Glu266Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251436 control chromosomes, predominantly at a frequency of 0.0029 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi-Goutieres Syndrome 1-AR (0.0017 vs 0.011), allowing no conclusion about variant significance. c.797A>G has been reported in the literature in two unspecified individuals without primary infomration (Dineiro_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Aicardi-Goutieres Syndrome 1-AR. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32483926). ClinVar contains an entry for this variant (Variation ID: 96242). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The E266G variant has not been published in association with Aicardi-Goutieres syndrome. However, the E266G variant has been published in association with systemic lupus erythematosus (SLE) (Namjou et al., 2011; Lee-Kirsch et al., 2007). Namjou et al., reports identifying the E266G variant in 5 patients of African decent diagnosed with SLE but not in ethnically matched controls (Namjou et al., 2011). This variant was also identified identified in members of the cohort of European decent but also within ethnically matched controls (Namjou et al., 2011). The NHLBI Exome Sequencing Project reports E266G was observed in 33/8600 (0.38%) alleles from individuals of European background, and the 1000 Genomes Project Consortium reports E266G was observed in 1/978 (0.1%) alleles from individuals of South Asian background. The E266G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aicardi Goutieres syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TREX1-related disorder Benign:1

Aug 09, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jun 04, 2022

Institute of Neurology, Charite University of Medicine

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.89
DANN	Benign	0.77
DEOGEN2	Benign	0.0091	T;.;.;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0079	N
LIST_S2	Benign	0.25	.;T;T;.;.;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0041	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.59	N;.;N;.;.;N
REVEL	Benign	0.032
Sift	Benign	0.47	T;.;T;.;.;T
Sift4G	Benign	0.21	T;.;T;.;.;T
Vest4		0.055
MVP		0.061
ClinPred		0.00062	T
GERP RS		-4.5
Varity_R		0.063
gMVP		0.29

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

Other links and lift over

dbSNP: rs55999987; hg19: chr3-48508851; COSMIC: COSV99062442; COSMIC: COSV99062442;