12-120739362-G-T
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting
The NM_000017.4(ACADS):c.1153G>T(p.Ala385Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,020 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000017.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACADS | ENST00000242592.9 | c.1153G>T | p.Ala385Ser | missense_variant | Exon 10 of 10 | 1 | NM_000017.4 | ENSP00000242592.4 | ||
ACADS | ENST00000411593.2 | c.1141G>T | p.Ala381Ser | missense_variant | Exon 10 of 10 | 2 | ENSP00000401045.2 |
Frequencies
GnomAD3 genomes AF: 0.000204 AC: 31AN: 152222Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248180Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 135036
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1460680Hom.: 0 Cov.: 33 AF XY: 0.0000124 AC XY: 9AN XY: 726658
GnomAD4 genome AF: 0.000203 AC: 31AN: 152340Hom.: 2 Cov.: 33 AF XY: 0.000255 AC XY: 19AN XY: 74502
ClinVar
Submissions by phenotype
Deficiency of butyryl-CoA dehydrogenase Pathogenic:1Uncertain:2
This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 385 of the ACADS protein (p.Ala385Ser). This variant is present in population databases (rs202124189, gnomAD 0.01%). This missense change has been observed in individuals with biochemical features of short-chain acyl-coenzyme A dehydrogenase deficiency (internal data). ClinVar contains an entry for this variant (Variation ID: 379779). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADS protein function. This variant disrupts the p.Ala385 amino acid residue in ACADS. Other variant(s) that disrupt this residue have been observed in individuals with ACADS-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
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Inborn genetic diseases Uncertain:1
The c.1153G>T (p.A385S) alteration is located in exon 10 (coding exon 10) of the ACADS gene. This alteration results from a G to T substitution at nucleotide position 1153, causing the alanine (A) at amino acid position 385 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/248180) total alleles studied. This alteration was detected in an individual with elevations in C4 acylcarnitines and ethylmalonic aciduria in combination with homozygous ACADS c.625G>A, a common variant that is not thought to be causative of short-chain acyl-CoA dehydrogenase deficiency (Pena, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32778825, 22241096) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at