rs1057516278
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000016.6(ACADM):c.1114dup(p.Ala372GlyfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
ACADM
NM_000016.6 frameshift
NM_000016.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.21
Genes affected
ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-75761289-T-TG is Pathogenic according to our data. Variant chr1-75761289-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 370160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.1114dup | p.Ala372GlyfsTer11 | frameshift_variant | 11/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.1114dup | p.Ala372GlyfsTer11 | frameshift_variant | 11/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251254Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135776
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461796Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727196
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74378
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:5
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Dec 07, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 23, 2023 | This variant is also known as c.1114–1115insG. This premature translational stop signal has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 23028790). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Ala372Glyfs*11) in the ACADM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). ClinVar contains an entry for this variant (Variation ID: 370160). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 09, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 19, 2016 | Variant summary: The ACADM c.1114dupG (p.Ala372Glyfs) variant results in a premature termination codon, predicted to cause a truncated or absent ACADM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP). The variant of interest was reported in one affected newborn via publications. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at