chr1-47416318-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PVS1_Supporting
The NM_012186.3(FOXE3):āc.3G>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000067 in 1,343,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_012186.3 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000662 AC: 1AN: 151088Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000671 AC: 8AN: 1192408Hom.: 0 Cov.: 30 AF XY: 0.00000687 AC XY: 4AN XY: 582512
GnomAD4 genome AF: 0.00000662 AC: 1AN: 151088Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73660
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: FOXE3 c.3G>C (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next downstream, in-frame ATG start site is at codon 7 (Exon 1), however, alternative FOXE3 transcripts have yet to be identified. Three of three in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 51214 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3G>C in individuals affected with Aortic Aneurysm, Familial Thoracic 11 and no experimental evidence demonstrating its impact on protein function have been reported in the literature. However, one ClinVar submitter has identified a start-loss variant in at least one individual with clinical features of FOXE3-related disorders (Invitae). Additionally, the variant has a non-damaging PoStaL score (0.411 compared to 0.4815 which corresponds to a 95% specificity in the test set (Takata_2021)). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Congenital primary aphakia;C1862839:Anterior segment dysgenesis Uncertain:1
This sequence change affects the initiator methionine of the FOXE3 mRNA. The next in-frame methionine is located at codon 7. This variant is present in population databases (no rsID available, gnomAD 0.007%). Disruption of the initiator codon has been observed in individual(s) with clinical features of autosomal dominant FOXE3-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 2143547). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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