rs148833270
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_033629.6(TREX1):c.869C>T(p.Pro290Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_033629.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TREX1 | NM_033629.6 | c.869C>T | p.Pro290Leu | missense_variant | 2/2 | ENST00000625293.3 | NP_338599.1 | |
ATRIP | NM_130384.3 | c.*1970C>T | 3_prime_UTR_variant | 13/13 | ENST00000320211.10 | NP_569055.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TREX1 | ENST00000625293.3 | c.869C>T | p.Pro290Leu | missense_variant | 2/2 | 6 | NM_033629.6 | ENSP00000486676.2 | ||
ATRIP | ENST00000320211.10 | c.*1970C>T | 3_prime_UTR_variant | 13/13 | 1 | NM_130384.3 | ENSP00000323099.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000638 AC: 16AN: 250958Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135738
GnomAD4 exome AF: 0.0000424 AC: 62AN: 1461384Hom.: 0 Cov.: 33 AF XY: 0.0000481 AC XY: 35AN XY: 727014
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152194Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2024 | Variant summary: TREX1 c.869C>T (p.Pro290Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 250958 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in TREX1 causing Aicardi-Goutieres Syndrome 1-AR (6.4e-05 vs 0.011), allowing no conclusion about variant significance. c.869C>T has been reported in the literature in an individuals affected with Systemic lupus erythematosus (Lee-Kirsch_2007). This report does not provide unequivocal conclusions about association of the variant with Aicardi-Goutieres Syndrome 1-AR. Publications report experimental evidence evaluating an impact on protein function, finding no effect of the variant on exonuclease activity or localization (Orebaugh_2013, Mohr_2021). The following publications have been ascertained in the context of this evaluation (PMID: 17660818, 23979357, 33476576). ClinVar contains an entry for this variant (Variation ID: 576299). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 11, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 290 of the TREX1 protein (p.Pro290Leu). This variant is present in population databases (rs148833270, gnomAD 0.02%). This missense change has been observed in individual(s) with systemic lupus erythermatosus (PMID: 17660818). ClinVar contains an entry for this variant (Variation ID: 576299). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at