rs55999987

chr3-48467452-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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). Synonymous variant affecting the same amino acid position (i.e. E266E) has been classified as Likely benign.

• 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:5 B:7
• 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 -9 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: {Uncertain_significance=5, Benign=1, Likely_benign=3}. 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. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TREX1	NM_033629.6	c.797A>G	p.Glu266Gly	missense_variant	2/2	ENST00000625293.3
ATRIP	NM_130384.3	c.*1898A>G		3_prime_UTR_variant	13/13	ENST00000320211.10
ATRIP-TREX1	NR_153405.1	n.4106A>G		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TREX1	ENST00000625293.3	c.797A>G	p.Glu266Gly	missense_variant	2/2		NM_033629.6	P1
ATRIP	ENST00000320211.10	c.*1898A>G		3_prime_UTR_variant	13/13	1	NM_130384.3	P1

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:5 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TREX1: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 24, 2013	- -

not specified Uncertain:2 Benign:1

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Aicardi Goutieres syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

Likely benign, no assertion criteria provided

research

Institute of Neurology, Charite University of Medicine

Jun 04, 2022

- -

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
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0041	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
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;