3-48467394-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_033629.6(TREX1):c.739G>C(p.Ala247Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,614,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A247V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

TREX1
NM_033629.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 1.90

Publications

8 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: Likely_benign. The variant received -4 ACMG points.

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, chilblain lupus 1, systemic lupus erythematosus, familial chilblain lupus.

BP4

Computational evidence support a benign effect (MetaRNN=0.019473463).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000433 (66/152346) while in subpopulation AFR AF = 0.00156 (65/41576). AF 95% confidence interval is 0.00126. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	HGVSp	Effect	Exon Rank	Protein
TREX1	NM_033629.6	MANE Select	c.739G>C	p.Ala247Pro	missense	Exon 2 of 2	NP_338599.1
ATRIP	NM_130384.3	MANE Select	c.*1840G>C		3_prime_UTR	Exon 13 of 13	NP_569055.1
TREX1	NM_007248.5		c.709G>C	p.Ala237Pro	missense	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.739G>C	p.Ala247Pro	missense	Exon 2 of 2	ENSP00000486676.2
TREX1	ENST00000444177.1	TSL:1	c.709G>C	p.Ala237Pro	missense	Exon 2 of 2	ENSP00000415972.1
TREX1	ENST00000433541.1	TSL:1	c.322G>C	p.Ala108Pro	missense	Exon 4 of 4	ENSP00000412404.1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000119

AC:

AN:

251366

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000944

AC:

138

AN:

1461858

Hom.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1112010

Other (OTH)

AF:

0.000315

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000433

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00156

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.000473

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:

0.0000792

Hom.:

Bravo

AF:

0.000552

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jul 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4

Apr 13, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 09, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Uncertain:1

Mar 19, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TREX1 c.739G>C (p.Ala247Pro) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 251366 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi-Goutieres Syndrome 1-AR (0.00012 vs 0.011), allowing no conclusion about variant significance. c.679G>A has been reported in the literature in cis with a VUS missense in one individual affected with SLE, without strong evidence for causality (Lee_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Aicardi-Goutieres Syndrome 1-AR. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17660818). ClinVar contains an entry for this variant (Variation ID: 586842). Based on the evidence outlined above, the variant was classified as uncertain significance.

TREX1-related disorder

Uncertain:1

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TREX1 c.739G>C variant is predicted to result in the amino acid substitution p.Ala247Pro. This variant has been reported in cis with a second variant c.844G>A, p.Gly282Ser in an individual with systemic lupus erythematosus (referred to as G227S+A247P on alternate transcript NM_033629, table S2, Lee-Kirsch et al. 2007. PubMed ID: 17660818). This variant is reported in 0.13% of alleles in individuals of African descent in gnomAD. Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

Uncertain:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 247 of the TREX1 protein (p.Ala247Pro). This variant is present in population databases (rs112741962, gnomAD 0.1%). This missense change has been observed in individual(s) with systemic lupus erythematosus (PMID: 17660818, 21270825). ClinVar contains an entry for this variant (Variation ID: 586842). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.024

Eigen

Benign

0.11

Eigen_PC

Benign

-0.066

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.50

M_CAP

Benign

0.026

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.82

PhyloP100

1.9

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.24

REVEL

Benign

0.25

Sift

Benign

0.031

Sift4G

Pathogenic

0.0

Vest4

0.49

MVP

0.58

ClinPred

0.12

GERP RS

4.2

Varity_R

0.17

gMVP

0.43

Mutation Taster

=2/98

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over