rs387907042
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_014049.5(ACAD9):c.797G>A(p.Arg266Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,990 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_014049.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACAD9 | NM_014049.5 | c.797G>A | p.Arg266Gln | missense_variant | 7/18 | ENST00000308982.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAD9 | ENST00000308982.12 | c.797G>A | p.Arg266Gln | missense_variant | 7/18 | 1 | NM_014049.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251372Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135872
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727220
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Acyl-CoA dehydrogenase 9 deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | research | Kids Research, The Children's Hospital at Westmead | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 23, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 21, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2022 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ACAD9 function (PMID: 25721401). 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 expected to disrupt ACAD9 protein function. ClinVar contains an entry for this variant (Variation ID: 30882). This missense change has been observed in individual(s) with ACAD9-related conditions (PMID: 21057504, 30025539, 31665838, 32313153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs387907042, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 266 of the ACAD9 protein (p.Arg266Gln). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at