rs863224844
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014049.5(ACAD9):βc.359delβ(p.Phe120SerfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000819 in 1,611,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.00035 ( 0 hom., cov: 32)
Exomes π: 0.000054 ( 0 hom. )
Consequence
ACAD9
NM_014049.5 frameshift
NM_014049.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.57
Genes affected
ACAD9 (HGNC:21497): (acyl-CoA dehydrogenase family member 9) This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-128895320-CT-C is Pathogenic according to our data. Variant chr3-128895320-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACAD9 | NM_014049.5 | c.359del | p.Phe120SerfsTer9 | frameshift_variant | 4/18 | ENST00000308982.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAD9 | ENST00000308982.12 | c.359del | p.Phe120SerfsTer9 | frameshift_variant | 4/18 | 1 | NM_014049.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000349 AC: 53AN: 151884Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000101 AC: 25AN: 247292Hom.: 0 AF XY: 0.0000899 AC XY: 12AN XY: 133486
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GnomAD4 exome AF: 0.0000541 AC: 79AN: 1459796Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 725916
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GnomAD4 genome AF: 0.000349 AC: 53AN: 151984Hom.: 0 Cov.: 32 AF XY: 0.000566 AC XY: 42AN XY: 74258
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Acyl-CoA dehydrogenase 9 deficiency Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 17, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 24, 2018 | The ACAD9 c.359delT (p.Phe120SerfsTer9) variant is a frameshift variant that is predicted to result in premature termination of the protein. This variant has not been reported in the literature; however an equivalent variant, c.358delT (p.Phe120SerfsTer9) has been reported in at least five studies and is found in a compound heterozygous state in a total of three individuals with ACAD9 deficiency (Lee et al. 2014; Collet et al. 2015; Schiff et al. 2015; Fragaki et al. 2017; Repp et al. 2018). Control data are unavailable for the p.Phe120SerfsTer9 variant, which is reported at a frequency of 0.000527 in the Latino population of the Genome Aggregation Database. Mitochondrial respiratory chain complex I activity was reduced in patient-derived muscle and heart tissue (Collet et al. 2015; Schiff et al. 2015; Fragaki et al. 2017). Based on the evidence, the p.Phe120SerfsTer9 variant is classified as likely pathogenic for ACAD9 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 23, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 30, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25721401, 28529009, 25326637, 31683770, 26669660, 30025539, 34440436, 34023438, 34204301) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Phe120Serfs*9) in the ACAD9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACAD9 are known to be pathogenic (PMID: 25721401). This variant is present in population databases (rs746304569, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with mitochondrial complex I deficiency (PMID: 25721401, 26669660, 28529009). This variant is also known as c.358delT. ClinVar contains an entry for this variant (Variation ID: 242524). For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial complex I deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 11, 2024 | Variant summary: ACAD9 c.359delT (p.Phe120SerfsX9) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0001 in 247292 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ACAD9 causing Mitochondrial Complex I Deficiency, Nuclear Type 20 (0.0001 vs 0.0011). c.359delT (also known as c.358delT) has been reported in the literature in individuals affected with Mitochondrial Complex I Deficiency and the variant segregated with disease (examples: Collet_2016, Fragaki_2017, Schiff_2015, and Barbosa-Gouveia_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34440436, 26669660, 28529009, 34023438, 25721401). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at