rs145285434
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_001243279.3(ACSF3):c.1081G>A(p.Gly361Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000868 in 1,613,348 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001243279.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152176Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250644Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135644
GnomAD4 exome AF: 0.0000855 AC: 125AN: 1461172Hom.: 1 Cov.: 48 AF XY: 0.0000977 AC XY: 71AN XY: 726954
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152176Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74336
ClinVar
Submissions by phenotype
Combined malonic and methylmalonic acidemia Pathogenic:1Uncertain:4
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This sequence change replaces glycine with serine at codon 361 of the ACSF3 protein (p.Gly361Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs145285434, ExAC 0.01%). This variant has been observed in combination with another ACSF3 variant in an individual affected with combined malonic and methylmalonic aciduria (PMID: 29858964). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
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not provided Pathogenic:1Uncertain:1
Identified in a patient with combined malonic and methylmalonic aciduria in the presence of a second ACSF3 variant in published literature (Levtova et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30740739) -
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not specified Uncertain:1
Variant summary: ACSF3 c.1081G>A (p.Gly361Ser) results in a non-conservative amino acid change located in the AMP-dependent synthetase/ligase (IPR000873) of the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250644 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACSF3 causing Combined Malonic And Methylmalonic Aciduria (0.0001 vs 0.0058), allowing no conclusion about variant significance. c.1081G>A has been reported in the literature in an individual affected with Combined Malonic And Methylmalonic Aciduria (Levtova_2019) without evidence of causality. This report does not provide unequivocal conclusions about association of the variant with Combined Malonic And Methylmalonic Aciduria. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30740739). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at