3-48466629-G-A

Variant names:

• chr3-48466629-G-A
• rs749323787
• NM_130384.3:c.*1075G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_033629.6(TREX1):​c.-26-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: TREX1 NM_033629.6 splice_acceptor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.18

Genes affected

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]

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-TREX1 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5, offset of 1, new splice context is: accccatgctcctctccaAGctc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 3-48466629-G-A is Pathogenic according to our data. Variant chr3-48466629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 632417.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATRIP	NM_130384.3	c.*1075G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000320211.10	NP_569055.1
TREX1	NM_033629.6	c.-26-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 1	ENST00000625293.3	NP_338599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATRIP	ENST00000320211.10	c.*1075G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_130384.3	ENSP00000323099.3
TREX1	ENST00000625293.3	c.-26-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 1	6	NM_033629.6	ENSP00000486676.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151822 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000760 AC: 19 AN: 249970 AF XY: 0.000126

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461842 Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31 AN XY: 727228

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000327 AC: 13 AN: 39700

Gnomad4 SAS exome AF: 0.000301 AC: 26 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53378

Gnomad4 NFE exome AF: 0.0000108 AC: 12 AN: 1112006

Gnomad4 Remaining exome AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 151940 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74254

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000583 AC: 0.000583204 AN: 0.000583204

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147167 AN: 0.0000147167

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000595 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

TREX1-related disorder Uncertain:2

Oct 09, 2023

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TREX1 c.-26-1G>A variant is located in the 5' untranslated region. Using the canonical transcript (NM_033629) this variant is located upstream of the start codon (c.-26-1G>A) and is predicted to weaken a cryptic splice site based on available splicing prediction programs (Alamut Visual v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. This variant has been reported in an individual undergoing sequencing for juvenile-onset systemic lupus erythematosus (described as "rs749323787", Charras et al. 2023. PubMed ID: 35532072). This variant is reported in 0.036% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Pathogenic:1

Mar 19, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with additional TREX1 variant(s) in patients with AicardiGoutieres syndrome, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 35551623); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: Oh2022[CaseReport], 37556020, 29159939, 35551623, 35532072) -

Aicardi-Goutieres syndrome 1 Pathogenic:1

Mar 11, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TREX1 c.-26-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of TREX1 function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 3' acceptor site. One predict the variant abolishes the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.6e-05 in 249970 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi Goutieres Syndrome 1, allowing no conclusion about variant significance. c.-26-1G>A has been reported in the literature at a compound heterozygous state with a second pathogenic variant in TREX1 in two individuals with Aicardi Goutieres Syndrome 1 (Zhang_2024), and with an apparently VUS variant (c.358_360dup, p.Asp120dup) in an individual with developmental delay and other clinical findings (Xiao_2018). Additionally, this variant was reported as a heterozygous genotype in an individual affected with Juvenile-onset systemic lupus erythematosus (Charras_2023) and annotated in a different transcript (NM_016381.5) as a missense variant of uncertain significance (c.139G>A, p.Gly47Ser). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35532072, 29159939, 39347527). ClinVar contains an entry for this variant (Variation ID: 632417). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 2
DS_AL_spliceai		0.92		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs749323787; hg19: chr3-48508028; COSMIC: COSV105881685; COSMIC: COSV105881685;