rs768884003
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000016.6(ACADM):c.757G>A(p.Glu253Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000016.6 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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.757G>A | p.Glu253Lys | missense_variant | Exon 9 of 12 | ENST00000370841.9 | NP_000007.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152132Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251378Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461776Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727192
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152132Hom.: 1 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74314
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:6
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This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 253 of the ACADM protein (p.Glu253Lys). This variant is present in population databases (rs768884003, gnomAD 0.006%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 20434380; internal data). ClinVar contains an entry for this variant (Variation ID: 226054). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACADM protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: ACADM c.757G>A (p.Glu253Lys) results in a conservative amino acid change located in the acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 8e-06 in 251378 control chromosomes (gnomAD). c.757G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Smith_2010, Gong_2021) and in one affected individual in the homozygous state (Tajima_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing that cells from a patient homozygous for the variant of interest had normal enzymatic activity in vitro (Tajima_2016), however the authors speculate that the assay conditions do not faithfully replicate what occurs in vivo, allowing no convincing conclusion about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 33841490, 20434380, 27856190). ClinVar contains an entry for this variant (Variation ID: 226054). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at