3-128879692-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014049.5(ACAD9):c.1A>G(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 0.0000171 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: 0.000017 (0 hom.)
• Consequence: ACAD9 NM_014049.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

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 3-128879692-A-G is Pathogenic according to our data. Variant chr3-128879692-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 242469.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>G	p.Met1?	start_lost	1/18	ENST00000308982.12
ACAD9	NM_001410805.1	c.-275A>G		5_prime_UTR_variant	1/17
ACAD9	NR_033426.2	n.73A>G		non_coding_transcript_exon_variant	1/18
ACAD9	XR_427367.4	n.73A>G		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD9	ENST00000308982.12	c.1A>G	p.Met1?	start_lost	1/18	1	NM_014049.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1460074 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726378

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: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 17, 2023

This sequence change affects the initiator methionine of the ACAD9 mRNA. The next in-frame methionine is located at codon 124. This variant is not present in population databases (gnomAD no frequency). 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: 242469). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.60	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.92	P;.
Vest4		0.91
MutPred		0.98		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.98
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs773949927; hg19: chr3-128598535;