rs121434275
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_000016.6(ACADM):āc.1124T>Cā(p.Ile375Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 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 (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I375M) has been classified as Uncertain significance.
Frequency
Consequence
NM_000016.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.1124T>C | p.Ile375Thr | missense_variant | 11/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.1124T>C | p.Ile375Thr | missense_variant | 11/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74370
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 05, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 375 of the ACADM protein (p.Ile375Thr). 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. 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. ClinVar contains an entry for this variant (Variation ID: 3589). This missense change has been observed in individual(s) with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 1684086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121434275, gnomAD 0.1%). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1991 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at