Genetic Variant TREX1:c.-34_-31dupCTGC (chr3-48466285-A-ACTGC) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_033629.6(TREX1):c.-34_-31dupCTGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000602 in 668,030 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

TREX1
NM_033629.6 5_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.630

Publications

0 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
hereditary breast carcinoma
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ATRIP links:

ATRIP-TREX1 (HGNC:):

ATRIP-TREX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00162 (246/152250) while in subpopulation AFR AF = 0.00515 (214/41562). AF 95% confidence interval is 0.00458. There are 0 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TREX1	NM_033629.6	MANE Select	c.-34_-31dupCTGC	5_prime_UTR	Exon 1 of 2	NP_338599.1	Q9NSU2-3
ATRIP	NM_130384.3	MANE Select	c.748_751dupCTGC	3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1
ATRIP	NM_032166.4		c.748_751dupCTGC	3_prime_UTR	Exon 12 of 12	NP_115542.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TREX1	ENST00000625293.3	TSL:6 MANE Select	c.-34_-31dupCTGC	5_prime_UTR	Exon 1 of 2	ENSP00000486676.2	Q9NSU2-3
TREX1	ENST00000433541.1	TSL:1	c.-353_-350dupCTGC	5_prime_UTR	Exon 2 of 4	ENSP00000412404.1	C9J052
ATRIP	ENST00000320211.10	TSL:1 MANE Select	c.748_751dupCTGC	3_prime_UTR	Exon 13 of 13	ENSP00000323099.3	Q8WXE1-1

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

246

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00516

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000302

AC:

156

AN:

515780

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

AN XY:

271820

show subpopulations

African (AFR)

AF:

0.00512

AC:

AN:

14854

American (AMR)

AF:

0.000653

AC:

AN:

27564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15428

East Asian (EAS)

AF:

0.000224

AC:

AN:

31316

South Asian (SAS)

AF:

0.0000192

AC:

AN:

52168

European-Finnish (FIN)

AF:

0.0000556

AC:

AN:

35944

Middle Eastern (MID)

AF:

0.000915

AC:

AN:

2186

European-Non Finnish (NFE)

AF:

0.000110

AC:

AN:

308094

Other (OTH)

AF:

0.000567

AC:

AN:

28226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.00162

AC:

246

AN:

152250

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00515

AC:

214

AN:

41562

American (AMR)

AF:

0.000458

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67998

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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3-48466285-ACTGCCTGC-ACTGCCTGCCTGC

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

Computational scores

Splicing

Publications

Other links and lift over