rs932525260
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000017.4(ACADS):c.974G>A(p.Arg325Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,230 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R325W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000017.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADS | NM_000017.4 | c.974G>A | p.Arg325Gln | missense_variant | 8/10 | ENST00000242592.9 | |
ACADS | NM_001302554.2 | c.962G>A | p.Arg321Gln | missense_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADS | ENST00000242592.9 | c.974G>A | p.Arg325Gln | missense_variant | 8/10 | 1 | NM_000017.4 | P1 | |
ACADS | ENST00000411593.2 | c.962G>A | p.Arg321Gln | missense_variant | 8/10 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251080Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135850
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461230Hom.: 0 Cov.: 40 AF XY: 0.00000688 AC XY: 5AN XY: 726948
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Deficiency of butyryl-CoA dehydrogenase Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Counsyl | Dec 07, 2017 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital | - | PM2_P+PM3+PM5+PP3+PP4 - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 25, 2017 | The R325Q variant in the ACADS gene has been reported previously in the compound heterozygous state in a patient diagnosed with short-chain acyl-CoA dehydrogenase (SCAD) deficiency after an abnormal newborn screen (Huang et al., 2016). The R325Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R325Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (R330C, R330H, E322K) have been reported in the Human Gene Mutation Database in association with SCAD deficiency (Stenson et al., 2014). A missense variant in the same residue (R325W) has also been reported, referred to as R301W, in an individual with increased ethylmalonic acid and undetectable short-chain acyl-CoA activity in fibroblasts, supporting a diagnosis of ethylmalonic aciduria/SCAD deficiency (Corydon et al., 2001). These variants further support the functional importance of this region of the protein. Therefore, we interpret R325Q as a likely pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at