chr3-48467513-GCTGCTGGCCCCACTGGGT-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM4PP5_Very_Strong

The ENST00000625293.3(TREX1):c.868_885delCCACTGGGTCTGCTGGCC(p.Pro290_Ala295del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.000088 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

TREX1
ENST00000625293.3 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 3.94

Publications

2 publications found

Variant links:

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]

TREX1 links:

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

ATRIP links:

ATRIP-TREX1 (HGNC:):

ATRIP-TREX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in ENST00000625293.3.

PP5

Variant 3-48467513-GCTGCTGGCCCCACTGGGT-G is Pathogenic according to our data. Variant chr3-48467513-GCTGCTGGCCCCACTGGGT-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 126393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000625293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TREX1	NM_033629.6	MANE Select	c.868_885delCCACTGGGTCTGCTGGCC	p.Pro290_Ala295del	conservative_inframe_deletion	Exon 2 of 2	NP_338599.1
ATRIP	NM_130384.3	MANE Select	c.1969_1986delCCACTGGGTCTGCTGGCC		3_prime_UTR	Exon 13 of 13	NP_569055.1
TREX1	NM_007248.5		c.838_855delCCACTGGGTCTGCTGGCC	p.Pro280_Ala285del	conservative_inframe_deletion	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TREX1	ENST00000625293.3	TSL:6 MANE Select	c.868_885delCCACTGGGTCTGCTGGCC	p.Pro290_Ala295del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000486676.2
TREX1	ENST00000444177.1	TSL:1	c.838_855delCCACTGGGTCTGCTGGCC	p.Pro280_Ala285del	conservative_inframe_deletion	Exon 2 of 2	ENSP00000415972.1
TREX1	ENST00000433541.1	TSL:1	c.451_468delCCACTGGGTCTGCTGGCC	p.Pro151_Ala156del	conservative_inframe_deletion	Exon 4 of 4	ENSP00000412404.1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000637

AC:

AN:

251074

AF XY:

0.0000516

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

133

AN:

1461712

Hom.:

AF XY:

0.0000853

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000854

AC:

AN:

1111992

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41454

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Aicardi-Goutieres syndrome 1 (5)

not provided (4)

Aicardi Goutieres syndrome (1)

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

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)

Systemic lupus erythematosus;C0024145:Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)

TREX1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.9

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over