3-48466313-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_033629.6(TREX1):c.-27+4A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000324 in 618,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_033629.6 splice_region, intron
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATRIP | NM_130384.3 | c.*759A>G | 3_prime_UTR_variant | Exon 13 of 13 | ENST00000320211.10 | NP_569055.1 | ||
TREX1 | NM_033629.6 | c.-27+4A>G | splice_region_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.*759A>G | 3_prime_UTR_variant | Exon 13 of 13 | 1 | NM_130384.3 | ENSP00000323099.3 | |||
TREX1 | ENST00000625293.3 | c.-27+4A>G | splice_region_variant, intron_variant | Intron 1 of 1 | 6 | NM_033629.6 | ENSP00000486676.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000324 AC: 2AN: 618018Hom.: 0 Cov.: 8 AF XY: 0.00000619 AC XY: 2AN XY: 323310
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Aicardi-Goutieres syndrome 1 Uncertain:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with TREX1-related conditions. Loss of function is generally associated with recessive disease while dominant negative variants are associated with dominant disease (OMIM, PMID: 21937424). However, loss of function is the mechanism of disease associated with heterozygous C-terminal frameshift variants identified in individuals with Retinal Vasculopathy with Cerebral Leukodystrophy (OMIM). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Aicardi-Goutieres syndrome is predominantly a recessive condition; however, there have been rare cases of a dominant form of the disease reported (OMIM). (I) 0218 - Non-coding variant without known or predicted effect. (I) 0252 - This variant is homozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable non-coding variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity in the literature. However, this variant was found to be biallelic in a research setting, in another individual with a typical Aicardi-Goutières syndrome phenotype (Professor Yanick Crow, personal communication). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by Sanger sequencing segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at