rs387906297
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000016.6(ACADM):βc.1102_1105delβ(p.Ala369LeufsTer18) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000161 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. Q367Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000016.6 frameshift
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.1102_1105del | p.Ala369LeufsTer18 | frameshift_variant | 11/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.1102_1105del | p.Ala369LeufsTer18 | frameshift_variant | 11/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251270Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135792
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461788Hom.: 0 AF XY: 0.0000165 AC XY: 12AN XY: 727200
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74330
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 04, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 30, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change creates a premature translational stop signal (p.Ala369Leufs*18) in the ACADM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 53 amino acid(s) of the ACADM protein. This variant is present in population databases (rs387906297, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 1356169, 1729890, 20434380). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1100_1103del. ClinVar contains an entry for this variant (Variation ID: 3592). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | May 02, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 27, 2021 | Variant summary: ACADM c.1102_1105delTTAG (p.Ala369LeufsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.2e-05 in 251270 control chromosomes. c.1102_1105delTTAG has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency and characteristic biochemical profiles of elevated C8 (octanoylcarnitine) and HG (hexanoylglycine) levels in plasma and urine respectively (example, Ding_1992, Kelly_1992, Smith_2010). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic with some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1992 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2020 | Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 53 amino acids are lost and replaced with 17 incorrect amino acids (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20639189, 20434380, 1356169, 1729890) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 08, 2012 | - - |
ACADM-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2023 | The ACADM c.1102_1105delTTAG variant is predicted to result in a frameshift and premature protein termination (p.Ala369Leufs*18). This variant, which has also been described as c.1100_1103del, has been reported with a second causative ACADM variant in individuals clinical and/or biochemical features consistent with medium chain acyl CoA dehydrogenase deficiency (MCADD) (Kelly et al. 1992. PubMed ID: 1356169; Smith et al. 2010. PubMed ID: 20434380). It has been reported to segregate with disease in at least one family (Ding et al. 1992. PubMed ID: 1729890). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-76226960-CAGTT-C). Other nonsense and frameshift variants both up- and downstream in ACADM have been reported to be causative for MCADD (Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ac/index.php). In summary, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at