rs772531600
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_000017.4(ACADS):c.821G>A(p.Gly274Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,246 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G274S) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADS | NM_000017.4 | c.821G>A | p.Gly274Asp | missense_variant | 7/10 | ENST00000242592.9 | |
ACADS | NM_001302554.2 | c.809G>A | p.Gly270Asp | missense_variant | 7/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADS | ENST00000242592.9 | c.821G>A | p.Gly274Asp | missense_variant | 7/10 | 1 | NM_000017.4 | P1 | |
ACADS | ENST00000411593.2 | c.809G>A | p.Gly270Asp | missense_variant | 7/10 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248314Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134570
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1458886Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0AN XY: 725918
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74390
ClinVar
Submissions by phenotype
Deficiency of butyryl-CoA dehydrogenase Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2016 | In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs772531600, ExAC 0.01%) but has not been reported in the literature in individuals with a ACADS-related disease. A different VUS change affecting the same codon, c.820G>A (p.Gly274Ser) has been reported in an individual affected with SCAD deficiency (PMID: 18523805). This sequence change replaces glycine with aspartic acid at codon 274 of the ACADS protein (p.Gly274Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at