12-120725888-G-A
Variant names:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate
The NM_000017.4(ACADS):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000658 in 152,028 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 Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
ACADS
NM_000017.4 start_lost
NM_000017.4 start_lost
Scores
6
5
5
Clinical Significance
Conservation
PhyloP100: 3.64
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 Uncertain_significance. Variant got 5 ACMG points.
PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 117 CDS bases. Genomic position: 120727096. Lost 0.094 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-120725888-G-A is Pathogenic according to our data. Variant chr12-120725888-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2709405.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ACADS | ENST00000242592.9 | c.3G>A | p.Met1? | start_lost | Exon 1 of 10 | 1 | NM_000017.4 | ENSP00000242592.4 | ||
ACADS | ENST00000411593.2 | c.3G>A | p.Met1? | start_lost | Exon 1 of 10 | 2 | ENSP00000401045.2 | |||
ACADS | ENST00000539690.1 | n.115G>A | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152028Hom.: 0 Cov.: 32
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1401346Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 694182
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152028Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74250
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Deficiency of butyryl-CoA dehydrogenase Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change affects the initiator methionine of the ACADS mRNA. The next in-frame methionine is located at codon 40. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant disrupts a region of the ACADS protein in which other variant(s) (p.Arg23Trp) have been observed in individuals with ACADS-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Uncertain
D;D
Polyphen
B;P
Vest4
MutPred
Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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