rs759158371
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000016.6(ACADM):c.1189T>A(p.Tyr397Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,552 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. Y397S) has been classified as Pathogenic.
Frequency
Consequence
NM_000016.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.1189T>A | p.Tyr397Asn | missense_variant | 11/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.1189T>A | p.Tyr397Asn | missense_variant | 11/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250034Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135194
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461552Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727060
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 22, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 26, 2023 | Variant summary: ACADM c.1189T>A (p.Tyr397Asn) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) 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 3.6e-05 in 250034 control chromosomes (gnomAD). c.1189T>A has been reported in the literature as a biallelic genotype in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Yokoi_2007, Woo_2011, Seo_2020, Li_2022). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing the variant had 0.9% residual activity when expressed in HEK293T cells (Hara_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26947917, 36068006, 32901917, 21239873, 18075239). Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 05, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Dec 20, 2023 | PS3, PM3_Strong, PM2, PM1, PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 397 of the ACADM protein (p.Tyr397Asn). This variant is present in population databases (rs759158371, gnomAD 0.05%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 18075239, 19064330, 21239873, 26947917). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1189A>T. ClinVar contains an entry for this variant (Variation ID: 226095). 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 not expected to disrupt ACADM protein function. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). This variant disrupts the p.Tyr397 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been observed in individuals with ACADM-related conditions (PMID: 18075239, 19064330, 21239873, 26947917; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at