rs875989860
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000016.6(ACADM):βc.1221_1222delβ(p.Arg408ThrfsTer6) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,607,496 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. Q407Q) has been classified as Likely benign.
Frequency
Consequence
NM_000016.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.1221_1222del | p.Arg408ThrfsTer6 | frameshift_variant | 12/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.1221_1222del | p.Arg408ThrfsTer6 | frameshift_variant | 12/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.0000117 AC: 17AN: 1455526Hom.: 0 AF XY: 0.0000166 AC XY: 12AN XY: 724468
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:3
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 | Baylor Genetics | Sep 06, 2018 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile416 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20434380, 23430840, 26947917). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 226069). This premature translational stop signal has been observed in individual(s) with MCAD deficiency (PMID: 20434380). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg408Thrfs*6) in the ACADM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the ACADM protein. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2023 | Frameshift variant predicted to result in protein truncation, as the last 14 amino acids are replaced with 5 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20434380, 32778825) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at