NM_033629.6:c.912G>A

Variant names:

• chr3-48467567-G-A
• rs3135945
• NM_033629.6:c.912G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033629.6(TREX1):​c.912G>A​(p.Leu304Leu) 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:7
• Conservation: PhyloP100: 0.637
• Publications: 15 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-TREX1 (HGNC:):

SHISA5 (HGNC:30376): (shisa family member 5) This gene encodes a member of the shisa family. The encoded protein is localized to the endoplasmic reticulum, and together with p53 induces apoptosis in a caspase-dependent manner. Alternative splicing results in multiple transcript variants. Related pseudogenes of this gene are found on chromosome X. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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	NM_033629.6	MANE Select	c.912G>A	p.Leu304Leu	synonymous	Exon 2 of 2	NP_338599.1	Q9NSU2-3
	ATRIP	NM_130384.3	MANE Select	c.*2013G>A		3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1
	TREX1	NM_007248.5		c.882G>A	p.Leu294Leu	synonymous	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.912G>A	p.Leu304Leu	synonymous	Exon 2 of 2	ENSP00000486676.2	Q9NSU2-3
	TREX1	ENST00000444177.1	TSL:1	c.882G>A	p.Leu294Leu	synonymous	Exon 2 of 2	ENSP00000415972.1	Q9NSU2-2
	TREX1	ENST00000433541.1	TSL:1	c.495G>A	p.Leu165Leu	synonymous	Exon 4 of 4	ENSP00000412404.1	C9J052

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

GnomAD2 exomes AF: 0.00943 AC: 2359 AN: 250178 AF XY: 0.00705

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 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

African (AFR) AF: 0.140 AC: 4682 AN: 33474

American (AMR) AF: 0.00633 AC: 283 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53106

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1111766

Other (OTH) AF: 0.00822 AC: 496 AN: 60374

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

African (AFR) AF: 0.129 AC: 5362 AN: 41520

American (AMR) AF: 0.0156 AC: 239 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68020

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0184 Hom.: 120

Bravo AF: 0.0432

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Aicardi Goutieres syndrome (1)
-	-	1	Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)
-	-	1	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	3.3
DANN	Benign	0.68
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3135945; hg19: chr3-48508966;