rs121908422
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_014384.3(ACAD8):c.905G>A(p.Arg302Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,614,016 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302P) has been classified as Uncertain significance.
Frequency
Consequence
NM_014384.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACAD8 | NM_014384.3 | c.905G>A | p.Arg302Gln | missense_variant | 8/11 | ENST00000281182.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAD8 | ENST00000281182.9 | c.905G>A | p.Arg302Gln | missense_variant | 8/11 | 1 | NM_014384.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251486Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135916
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461890Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727248
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74306
ClinVar
Submissions by phenotype
Deficiency of isobutyryl-CoA dehydrogenase Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 21, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ACAD8 function (PMID: 12359132, 16857760). 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 ACAD8 protein function. ClinVar contains an entry for this variant (Variation ID: 5359). This missense change has been observed in individuals with isobutyryl-CoA dehydrogenase deficiency (PMID: 12359132, 31813752). This variant is present in population databases (rs121908422, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 302 of the ACAD8 protein (p.Arg302Gln). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2002 | - - |
not provided Uncertain:1
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Apr 21, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at