rs786204691
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000017.4(ACADS):c.682_683del(p.Glu228ArgfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
ACADS
NM_000017.4 frameshift
NM_000017.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.61
Genes affected
ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]
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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
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-120738335-AAG-A is Pathogenic according to our data. Variant chr12-120738335-AAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADS | NM_000017.4 | c.682_683del | p.Glu228ArgfsTer16 | frameshift_variant | 6/10 | ENST00000242592.9 | |
ACADS | NM_001302554.2 | c.670_671del | p.Glu224ArgfsTer16 | frameshift_variant | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADS | ENST00000242592.9 | c.682_683del | p.Glu228ArgfsTer16 | frameshift_variant | 6/10 | 1 | NM_000017.4 | P1 | |
ACADS | ENST00000411593.2 | c.670_671del | p.Glu224ArgfsTer16 | frameshift_variant | 6/10 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1461868Hom.: 0 AF XY: 0.0000344 AC XY: 25AN XY: 727236
GnomAD4 exome
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727236
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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33
Bravo
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of butyryl-CoA dehydrogenase Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Dec 16, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2023 | This sequence change creates a premature translational stop signal (p.Glu228Argfs*16) in the ACADS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADS are known to be pathogenic (PMID: 12736383, 18523805). ClinVar contains an entry for this variant (Variation ID: 189093). This premature translational stop signal has been observed in individual(s) with clinical features of ACADS-related conditions (PMID: 22241096). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. - |
ACADS-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 20, 2023 | The ACADS c.682_683delGA variant is predicted to result in a frameshift and premature protein termination (p.Glu228Argfs*16). This variant was reported along with another potentially causative variant in an individual with short-chain acyl-CoA-dehydrogenase deficiency (Pena. 2012. PubMed ID: 22241096). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ACADS are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2014 | The c.682_683delGA mutation in the ACADS gene has been reported previously in association with short chain acyl-CoA dehydrogenase deficiency (Pena et al., 2012). The deletion causes a frameshift starting with codon Glutamic Acid 228, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Glu228ArgfsX16. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The surrounding sequence GAAA{delGA}AGAC. The variant is found in ACADS panel(s). - |
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