rs1553123858
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5
The NM_000016.6(ACADM):āc.473A>Gā(p.Tyr158Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,692 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y158H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000016.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADM | NM_000016.6 | c.473A>G | p.Tyr158Cys | missense_variant | 7/12 | ENST00000370841.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADM | ENST00000370841.9 | c.473A>G | p.Tyr158Cys | missense_variant | 7/12 | 1 | NM_000016.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457692Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725124
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 01, 2022 | This missense change has been observed in individual(s) with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (PMID: 23509891, 31012112). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Tyr158 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19224950, 24718418). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 550256). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the ACADM protein (p.Tyr158Cys). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at