chr3-48466629-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PP3_Moderate
The NM_033629.6(TREX1):c.-26-1G>A variant causes a splice acceptor 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
Consequence
NM_033629.6 splice_acceptor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TREX1 | NM_033629.6 | c.-26-1G>A | splice_acceptor_variant | ENST00000625293.3 | |||
ATRIP | NM_130384.3 | c.*1075G>A | 3_prime_UTR_variant | 13/13 | ENST00000320211.10 | ||
ATRIP-TREX1 | NR_153405.1 | n.3284-1G>A | splice_acceptor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TREX1 | ENST00000625293.3 | c.-26-1G>A | splice_acceptor_variant | NM_033629.6 | P1 | ||||
ATRIP | ENST00000320211.10 | c.*1075G>A | 3_prime_UTR_variant | 13/13 | 1 | NM_130384.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151822Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000760 AC: 19AN: 249970Hom.: 0 AF XY: 0.000126 AC XY: 17AN XY: 135410
GnomAD4 exome AF: 0.0000376 AC: 55AN: 1461842Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727228
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151940Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4AN XY: 74254
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 09, 2023 | Reported in the published literature as a heterozygous variant in a patient with juvenile-onset systemic lupus erythematosus (Charras et al., 2023) and in another individual with recurrent fevers (Oh et al., 2022).; 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], 35532072) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2023 | Variant summary: TREX1 c.-26-1G>A alters a conserved nucleotide 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. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 3' splicing acceptor site. One predict the variant abolishes the canonical 3' splicing 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. As the prevalence of Aicardi Goutieres Syndrome 1 attributed to TREX1 gene is unknown, this frequency does not allow conclusions about variant significance. c.-26-1G>A has been reported in the literature as a heterozygous genotype in an individual reportedly affected with Juvenile-onset systemic lupus erythematosus (jSLE) (example, Charras_2023) and annotated in a different transcript (NM_016381.5) as a missense variant of uncertain significance (c.139G>A, p.Gly47Ser) in compound heterozygosity with a different TREX1 variant (c.358_360dup, p.Asp120dup) in an individual with developmental delay and other clinical findings (example, Xiao_2018). These reports do not provide unequivocal conclusions about association of the variant with Aicardi Goutieres Syndrome 1. 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). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, one submitter classified the variant as benign, and a third submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
TREX1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Oct 09, 2023 | - - |
Aicardi-Goutieres syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 13, 2018 | The TREX1 c.-26-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change. No publications were found based on this search. Due to the potential impact of splice acceptor variants and the lack of clarifying evidence, this variant is classified as a variant of uncertain significance but suspicious for pathogenicity for Aicardi-Goutieres Syndrome. - |
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at