rs886038214
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_000018.4(ACADVL):c.1533G>A(p.Arg511=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Genomes: not found (cov: 32)
Consequence
ACADVL
NM_000018.4 splice_region, synonymous
NM_000018.4 splice_region, synonymous
Scores
2
Splicing: ADA: 0.004835
2
Clinical Significance
Conservation
PhyloP100: 1.45
Genes affected
ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
?
Variant 17-7224321-G-A is Benign according to our data. Variant chr17-7224321-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 254695.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=1.45 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.1533G>A | p.Arg511= | splice_region_variant, synonymous_variant | 16/20 | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.1533G>A | p.Arg511= | splice_region_variant, synonymous_variant | 16/20 | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely benign
Submissions summary: Uncertain:1Benign:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Dec 14, 2022 | The c.1533G>A (p.Arg511=) variant is a synonymous (silent) variant that is not predicted by (SpliceAI, MaxEntScn, NNSplice) to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). This variant is absent from gnomAD v2.1.1; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 8, 2021) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 27, 2022 | ClinVar contains an entry for this variant (Variation ID: 254695). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 511 of the ACADVL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ACADVL protein. It affects a nucleotide within the consensus splice site. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at