chr3-128879694-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_014049.5(ACAD9):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,096 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: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ACAD9
NM_014049.5 start_lost
NM_014049.5 start_lost
Scores
5
7
4
Clinical Significance
Conservation
PhyloP100: 2.77
Genes affected
ACAD9 (HGNC:21497): (acyl-CoA dehydrogenase family member 9) This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-128879694-G-A is Pathogenic according to our data. Variant chr3-128879694-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1451006.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACAD9 | NM_014049.5 | c.3G>A | p.Met1? | start_lost | 1/18 | ENST00000308982.12 | |
ACAD9 | NM_001410805.1 | c.-273G>A | 5_prime_UTR_variant | 1/17 | |||
ACAD9 | NR_033426.2 | n.75G>A | non_coding_transcript_exon_variant | 1/18 | |||
ACAD9 | XR_427367.4 | n.75G>A | non_coding_transcript_exon_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAD9 | ENST00000308982.12 | c.3G>A | p.Met1? | start_lost | 1/18 | 1 | NM_014049.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460096Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726390
GnomAD4 exome
AF:
AC:
2
AN:
1460096
Hom.:
Cov.:
31
AF XY:
AC XY:
2
AN XY:
726390
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 20, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the initiator methionine in ACAD9. If translation initiates from the next in-frame methionine, the ACAD9 protein would no longer include the region containing the p.Phe44 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with ACAD9-related conditions (PMID: 21057504), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Disruption of the initiator codon ‚Äãhas been observed in individual(s) with mitochondrial complex I deficiency (PMID: 26669660, 30025539). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the ACAD9 mRNA. The next in-frame methionine is located at codon p.Met124. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Pathogenic
D;D
Sift4G
Benign
T;D
Polyphen
P;.
Vest4
MutPred
Loss of disorder (P = 0.038);Loss of disorder (P = 0.038);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.