rs3135945

chr3-48467567-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033629.6(TREX1):c.912G>A(p.Leu304=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,613,512 control chromosomes in the GnomAD database, including 713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L304L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.037 (372 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (341 hom.)
• Consequence: TREX1 NM_033629.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.637

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-TREX1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 3-48467567-G-A is Benign according to our data. Variant chr3-48467567-G-A is described in ClinVar as [Benign]. Clinvar id is 262243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48467567-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.637 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.126 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TREX1	NM_033629.6	c.912G>A	p.Leu304=	synonymous_variant	2/2	ENST00000625293.3
ATRIP	NM_130384.3	c.*2013G>A		3_prime_UTR_variant	13/13	ENST00000320211.10
ATRIP-TREX1	NR_153405.1	n.4221G>A		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TREX1	ENST00000625293.3	c.912G>A	p.Leu304=	synonymous_variant	2/2		NM_033629.6	P1
ATRIP	ENST00000320211.10	c.*2013G>A		3_prime_UTR_variant	13/13	1	NM_130384.3	P1

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5667 AN: 152150 Hom.: 371 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00943 AC: 2359 AN: 250178 Hom.: 155 AF XY: 0.00705 AC XY: 955 AN XY: 135404

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00550

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.00394 AC: 5752 AN: 1461244 Hom.: 341 Cov.: 33 AF XY: 0.00329 AC XY: 2394 AN XY: 726912

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.00633

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000197

Gnomad4 OTH exome AF: 0.00822

GnomAD4 genome AF: 0.0373 AC: 5679 AN: 152268 Hom.: 372 Cov.: 33 AF XY: 0.0355 AC XY: 2646 AN XY: 74450

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0185 Hom.: 101

Bravo AF: 0.0432

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Aicardi Goutieres syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	3.3
Dann	Benign	0.68

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

LitVar

Other links and lift over

dbSNP: rs3135945; hg19: chr3-48508966;