rs77371662
Variant names:
Variant summary
Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM4_SupportingPP5_Moderate
The NM_033629.6(TREX1):c.366_368dupGGC(p.Ala123dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A123A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
TREX1
NM_033629.6 disruptive_inframe_insertion
NM_033629.6 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.15
Publications
0 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 cancerInheritance: AD Classification: MODERATE Submitted by: G2P
- Seckel syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary breast carcinomaInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 7 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 16 uncertain in NM_033629.6
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_033629.6. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 3-48467020-T-TGGC is Pathogenic according to our data. Variant chr3-48467020-T-TGGC is described in ClinVar as Pathogenic. ClinVar VariationId is 126386.Status of the report is criteria_provided_single_submitter, 1 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 | MANE Select | c.366_368dupGGC | p.Ala123dup | disruptive_inframe_insertion | Exon 2 of 2 | NP_338599.1 | Q9NSU2-3 | ||
| ATRIP | MANE Select | c.*1467_*1469dupGGC | 3_prime_UTR | Exon 13 of 13 | NP_569055.1 | Q8WXE1-1 | |||
| TREX1 | c.336_338dupGGC | p.Ala113dup | disruptive_inframe_insertion | Exon 2 of 2 | NP_009179.2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TREX1 | TSL:6 MANE Select | c.366_368dupGGC | p.Ala123dup | disruptive_inframe_insertion | Exon 2 of 2 | ENSP00000486676.2 | Q9NSU2-3 | ||
| TREX1 | TSL:1 | c.336_338dupGGC | p.Ala113dup | disruptive_inframe_insertion | Exon 2 of 2 | ENSP00000415972.1 | Q9NSU2-2 | ||
| TREX1 | TSL:1 | c.-52_-50dupGGC | 5_prime_UTR | Exon 4 of 4 | ENSP00000412404.1 | C9J052 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461616Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727132 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1461616
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
727132
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53148
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
2
AN:
1112008
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
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2
3
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0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
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8
10
<30
30-35
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Age
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
1
-
-
Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)
-
-
-
Aicardi-Goutieres syndrome 1 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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