3-128879692-A-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_014049.5(ACAD9):c.1A>T(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 0.00000342 in 1,460,074 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: 0.0000034 ( 0 hom. )
Consequence
ACAD9
NM_014049.5 start_lost
NM_014049.5 start_lost
Scores
5
4
7
Clinical Significance
Conservation
PhyloP100: 2.52
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 3-128879692-A-T is Pathogenic according to our data. Variant chr3-128879692-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1439431.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.1A>T | p.Met1? | start_lost | 1/18 | ENST00000308982.12 | |
ACAD9 | NM_001410805.1 | c.-275A>T | 5_prime_UTR_variant | 1/17 | |||
ACAD9 | NR_033426.2 | n.73A>T | non_coding_transcript_exon_variant | 1/18 | |||
ACAD9 | XR_427367.4 | n.73A>T | non_coding_transcript_exon_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACAD9 | ENST00000308982.12 | c.1A>T | p.Met1? | start_lost | 1/18 | 1 | NM_014049.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249332Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135200
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460074Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726378
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GnomAD4 genome ? Cov.: 33
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33
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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 | Jan 09, 2024 | This sequence change affects the initiator methionine of the ACAD9 mRNA. The next in-frame methionine is located at codon 124. This variant is present in population databases (rs773949927, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with mitochondrial complex I deficiency (PMID: 26669660, 30025539). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1439431). This variant disrupts a region of the ACAD9 protein in which other variant(s) (p.Phe44Ile) have been observed in individuals with ACAD9-related conditions (PMID: 21057504). 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
Benign
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
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 helix (P = 0.0033);Loss of helix (P = 0.0033);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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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