chr3-128896491-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_014049.5(ACAD9):c.509C>T(p.Ala170Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,070 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A170A) has been classified as Benign.
Frequency
Consequence
NM_014049.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACAD9 | NM_014049.5 | c.509C>T | p.Ala170Val | missense_variant | 5/18 | ENST00000308982.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAD9 | ENST00000308982.12 | c.509C>T | p.Ala170Val | missense_variant | 5/18 | 1 | NM_014049.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251434Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135890
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727242
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Acyl-CoA dehydrogenase 9 deficiency Pathogenic:1Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 13, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 10, 2022 | - - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 170 of the ACAD9 protein (p.Ala170Val). This variant is present in population databases (rs762521317, gnomAD 0.003%). This missense change has been observed in individual(s) with ACAD9-related conditions (PMID: 27233227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372249). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACAD9 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2020 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30025539, 27233227, 28070495) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 29, 2023 | Variant summary: ACAD9 c.509C>T (p.Ala170Val) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251434 control chromosomes (gnomAD). c.509C>T has been reported in the literature as a compound heterozygous genotype in two siblings affected with left ventricular hypertropy (Dewulf_2016), a presentation of Mitochondrial Complex I Deficiency, Nuclear Type 20. These data indicate that the variant may be associated with disease. 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: 27233227). Five ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, one as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at