rs78846775

Positions:

• chr3-48467253-G-A
• chr3-48467253-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_033629.6(TREX1):​c.598G>A​(p.Asp200Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D200H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.93

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity TREX1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_033629.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801
• PP5: Variant 3-48467253-G-A is Pathogenic according to our data. Variant chr3-48467253-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4184.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-48467253-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREX1	NM_033629.6	c.598G>A	p.Asp200Asn	missense_variant	2/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*1699G>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.598G>A	p.Asp200Asn	missense_variant	2/2	6	NM_033629.6	ENSP00000486676.2
ATRIP	ENST00000320211.10	c.*1699G>A		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi-Goutieres syndrome 1, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 16, 2011

- -

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

Mar 14, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TREX1 function (PMID: 18805785). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 4184). This missense change has been observed in individual(s) with Aicardi-Goutieres syndrome (PMID: 17357087, 20131292). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 200 of the TREX1 protein (p.Asp200Asn). -

Aicardi-Goutieres syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

Mar 13, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;T;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.77	.;T;T;.;.;T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.9	D;.;D;.;.;D
REVEL	Uncertain	0.63
Sift	Benign	0.032	D;.;D;.;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;.;D
Vest4		0.91
MVP		0.96
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs78846775; hg19: chr3-48508652;