3-128879694-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460096 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726390

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.61	N;N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.067	T;D
Polyphen		0.92	P;.
Vest4		0.89
MutPred		0.98		Loss of disorder (P = 0.038);Loss of disorder (P = 0.038);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-128598537;