1-75762744-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000016.6(ACADM):āc.1247T>Cā(p.Ile416Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000256 in 1,604,486 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I416I) has been classified as Likely benign.
Frequency
Consequence
NM_000016.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.1247T>C | p.Ile416Thr | missense_variant | Exon 12 of 12 | ENST00000370841.9 | NP_000007.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249404Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135186
GnomAD4 exome AF: 0.0000227 AC: 33AN: 1452346Hom.: 0 Cov.: 28 AF XY: 0.0000277 AC XY: 20AN XY: 722962
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74336
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:1Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 416 of the ACADM protein (p.Ile416Thr). This variant is present in population databases (rs760892123, gnomAD 0.006%). This missense change has been observed in individual(s) with mildly elevated levels of C8 and MCAD deficiency (PMID: 20434380, 23430840, 26947917; Invitae). ClinVar contains an entry for this variant (Variation ID: 203543). 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 ACADM protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect ACADM function (PMID: 26947917). For these reasons, this variant has been classified as Pathogenic. -
- -
not specified Uncertain:1
Variant summary: ACADM c.1247T>C (p.Ile416Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249404 control chromosomes (gnomAD), however the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1247T>C has been reported in the literature in newborns and other individuals suspected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (example: Smith_2010, Couce_2011, Couce_2013, Hara_2016, Tajima_2016, Adhikari_2020), but these data do not allow any conclusion about variant significance. Experimental evidence evaluating an impact on protein function demonstrated the variant has near normal residual enzymatic activity and thermal stability (Hara_2016). Three ClinVar submitters have assessed this variant since 2014: two have classified this variant as uncertain significance and one has classified it as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance. -
See cases Uncertain:1
ACMG classification criteria: PS3, PS4, PM2 -
not provided Uncertain:1
The I416T missense change in the ACADM gene has not been reported as a benign polymorphism. It has been reported previously in three patients detected by positive newborn screening results for medium chain acyl-CoA dehydrogenase (MCAD) deficiency who also harbored the K329E mutation (Smith et al., 2010 Couce et al., 2011). Biochemical analyses on these patients and in-silico analysis of I416T led the authors to conclude that this missense change was a variant of unknown significance. I416T is a non-conservative amino acid change in that a non-polar Isoleucine residue is replaced by a polar Threonine residue. This change occurs at a position that is highly conserved in the ACADM protein in mammals; however, this position is not highly conserved outside mammals or in related proteins. Multiple in-silico analysis models predict that I416T is a benign sequence change. Therefore, based on the currently available information, it is unclear whether I416T is a disease-causing mutation or a rare benign variant. The variant is found in ACADM panel(s). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at