NM_033629.6:c.52G>A

Variant names:

• chr3-48466707-G-A
• rs121908117
• NM_033629.6:c.52G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_033629.6(TREX1):​c.52G>A​(p.Asp18Asn) 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 (★★). ClinVar reports functional evidence for this variant: "SCV000329899: Published functional studies demonstrate a dominant-negative effect as variant protein forms heterodimers with wild type that are deficient at degrading double-stranded DNA and inhibit double-stranded DNA degradation activity of the TREX1 wild type enzyme (Lehtinen et al., 2008" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D18D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 4.84
• Publications: 76 publications found

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 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ATRIP-TREX1 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329899: Published functional studies demonstrate a dominant-negative effect as variant protein forms heterodimers with wild type that are deficient at degrading double-stranded DNA and inhibit double-stranded DNA degradation activity of the TREX1 wild type enzyme (Lehtinen et al., 2008; Lee-Kirsch et al., 2007); SCV000960511: Experimental studies have shown that this missense change affects TREX1 function (PMID: 17440703, 18805785, 20871604, 25848017).
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 0.29847 (below the threshold of 3.09). GenCC associations: The gene is linked to Aicardi-Goutieres syndrome 1, Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, familial chilblain lupus, chilblain lupus 1, systemic lupus erythematosus, TREX1-related type 1 interferonopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 3-48466707-G-A is Pathogenic according to our data. Variant chr3-48466707-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 4185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033629.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	NM_033629.6	MANE Select	c.52G>A	p.Asp18Asn	missense	Exon 2 of 2	NP_338599.1	Q9NSU2-3
	ATRIP	NM_130384.3	MANE Select	c.*1153G>A		3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1
	TREX1	NM_007248.5		c.22G>A	p.Asp8Asn	missense	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.52G>A	p.Asp18Asn	missense	Exon 2 of 2	ENSP00000486676.2	Q9NSU2-3
	TREX1	ENST00000444177.1	TSL:1	c.22G>A	p.Asp8Asn	missense	Exon 2 of 2	ENSP00000415972.1	Q9NSU2-2
	ATRIP	ENST00000320211.10	TSL:1 MANE Select	c.*1153G>A		3_prime_UTR	Exon 13 of 13	ENSP00000323099.3	Q8WXE1-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Aicardi-Goutieres syndrome 1, autosomal dominant (1)
1	-	-	Chilblain lupus (1)
1	-	-	Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)
1	-	-	not provided (1)
-	-	-	Aicardi-Goutieres syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.83	D
PhyloP100		4.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.013	D
Sift4G	Pathogenic	0.0	D
Vest4		0.90
MVP		0.99
ClinPred		1.0	D
GERP RS		5.3
BranchPoint Hunter		0.0
PromoterAI		0.068	Neutral
Varity_R		0.63
gMVP		0.70
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908117; hg19: chr3-48508106;