rs765356942
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM3_SupportingPP4_ModeratePP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1269G>A (NM_000018.4) variant in ACADVL is a synonymous variant which occurs in the final nucleotide of exon 12, a position that is generally considered highly conserved. At least one patient with this variant displayed reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels in lymphocytes, which is highly specific for VLCAD deficiency (PP4_moderate, PMID:30194637). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000046 (0.0046%) in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.79 for donor loss, predicting that the variant disrupts the donor splice site of intron 12 of ACADVL (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8338048/MONDO:0008723/021
Frequency
Consequence
NM_000018.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251448Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461864Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727234
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:1Uncertain:3
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The c.1269G>A (NM_000018.4) variant in ACADVL is a synonymous variant which occurs in the final nucleotide of exon 12, a position that is generally considered highly conserved. At least one patient with this variant displayed reduced very long chain acyl-CoA dehydrogenase (VLCAD) enzyme levels in lymphocytes, which is highly specific for VLCAD deficiency (PP4_moderate, PMID: 30194637). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000046 (0.0046%) in European (non-Finnish) population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.79 for donor loss, predicting that the variant disrupts the donor splice site of intron 12 of ACADVL (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_supporting, PP3, PP4_moderate (ACADVL VCEP specifications version 1; approved November 9, 2021). -
This sequence change affects codon 423 of the ACADVL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ACADVL protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is present in population databases (rs765356942, gnomAD 0.006%). This variant has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 9973285, 30194637). ClinVar contains an entry for this variant (Variation ID: 569548). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at