chr3-48466945-G-A

Position:

• chr3-48466945-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_033629.6(TREX1):​c.290G>A​(p.Arg97His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,611,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (1 hom.)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1
• Conservation: PhyloP100: 3.42

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 3-48466945-G-A is Pathogenic according to our data. Variant chr3-48466945-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225498.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39235663). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREX1	NM_033629.6	c.290G>A	p.Arg97His	missense_variant	2/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*1391G>A		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3	c.290G>A	p.Arg97His	missense_variant	2/2	6	NM_033629.6	ENSP00000486676.2
ATRIP	ENST00000320211.10	c.*1391G>A		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099.3

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000601 AC: 15 AN: 249418 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135034

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1459402 Hom.: 1 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 726164

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74488

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aicardi-Goutieres syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2024	Variant summary: TREX1 c.290G>A (p.Arg97His) results in a non-conservative amino acid change located in the Exonuclease domain (IPR013520) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 249418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi Goutieres Syndrome 1, allowing no conclusion about variant significance. c.290G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Aicardi Goutieres Syndrome 1 (e.g. Ellyard_2014, Olivieri_2013, van der Ven_2021, Kuang_2022). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence, demonstrating decreased enzyme activity in an in vitro expression system and lymphocyte function changes in patient derived cells (Olivieri_2013, Pulliero_2012). The following publications have been ascertained in the context of this evaluation (PMID: 31589614, 25138095, 23918923, 22367235, 34490615, 35803721). ClinVar contains an entry for this variant (Variation ID: 225498). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 20, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with TREX1-related conditions. Loss of function is generally associated with recessive disease, while dominant negative variants are associated with dominant disease (OMIM, PMID: 21937424). However, loss of function is the mechanism of disease associated with heterozygous C-terminal frameshift variants identified in individuals with retinal vasculopathy with cerebral leukodystrophy (OMIM). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Aicardi-Goutieres syndrome is predominantly a recessive condition; however, there have been rare cases of a dominant form of the disease reported (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (16 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v3) (highest allele count: 2 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, two alternative changes with higher Grantham scores, p.(Arg97Ser) and p.(Arg97Cys), have been reported once each as a VUS (ClinVar). (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS and as likely pathogenic and pathogenic, with limited clinical information provided (ClinVar, LOVD). However, it has also been observed in two compound heterozygous individuals with Aicardi-Goutières syndrome (PMID: 35803721, PMID: 31130681), a homozygous individual with cerebral systemic lupus erthematosus (PMID: 25138095) and another homozygous individual with severe global developmental delay, leukodystrophy and cerebellar hypoplasia (PMID: 31056085). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated a 20-fold reduction in exonuclease activity compared to wildtype cells (PMID: 25138095). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2020	- -

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

Jan 29, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 97 of the TREX1 protein (p.Arg97His). This variant is present in population databases (rs200773268, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive Aicardi-Goutieres syndrome and/or systemic lupus erythematosus (PMID: 3580372, 23918923, 25138095, 31130681, 34490615, 35803721). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225498). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TREX1 function (PMID: 22367235, 25138095). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	0.55	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.0	.;N
REVEL	Uncertain	0.59
Sift	Benign	0.072	.;T
Sift4G	Uncertain	0.0070	.;D
Vest4		0.68
MVP		0.93
ClinPred		0.68	D
GERP RS		5.0
Varity_R		0.080
gMVP		0.43

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: rs200773268; hg19: chr3-48508344;