3-128909019-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_014049.5(ACAD9):c.1405C>T(p.Arg469Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000726 in 1,614,176 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R469Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 2 hom. )

Consequence

ACAD9
NM_014049.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:2

Conservation

PhyloP100: 0.933

Variant links:

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]

ACAD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PP5

Variant 3-128909019-C-T is Pathogenic according to our data. Variant chr3-128909019-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214007.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, Likely_pathogenic=2}.

BP4

Computational evidence support a benign effect (MetaRNN=0.20564798). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD9	NM_014049.5 link	c.1405C>T	p.Arg469Trp	missense_variant	Exon 14 of 18	ENST00000308982.12	NP_054768.2	Q9H845
ACAD9	NM_001410805.1 link	c.1036C>T	p.Arg346Trp	missense_variant	Exon 13 of 17		NP_001397734.1
ACAD9	XM_024453484.2 link	c.1036C>T	p.Arg346Trp	missense_variant	Exon 14 of 18		XP_024309252.1
ACAD9	NR_033426.2 link	n.1653C>T		non_coding_transcript_exon_variant	Exon 14 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982.12 link	c.1405C>T	p.Arg469Trp	missense_variant	Exon 14 of 18	1	NM_014049.5	ENSP00000312618.7		Q9H845

Frequencies

GnomAD3 genomes

AF:

0.000414

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000779

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000398

AC:

100

AN:

251318

AF XY:

0.000434

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000783

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000759

AC:

1109

AN:

1461820

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

537

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

AC:

AN:

33480

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

44724

Gnomad4 ASJ exome

AF:

0.0000765

AC:

AN:

26136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39700

Gnomad4 SAS exome

AF:

0.0000232

AC:

AN:

86258

Gnomad4 FIN exome

AF:

0.000131

AC:

AN:

53354

Gnomad4 NFE exome

AF:

0.000972

AC:

1081

AN:

1112006

Gnomad4 Remaining exome

AF:

0.000215

AC:

AN:

60394

Heterozygous variant carriers

152

227

303

379

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000414

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000168

AC:

0.000168342

AN:

0.000168342

Gnomad4 AMR

AF:

0.0000653

AC:

0.0000653168

AN:

0.0000653168

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.0000942

AC:

0.0000941797

AN:

0.0000941797

Gnomad4 NFE

AF:

0.000779

AC:

0.000779045

AN:

0.000779045

Gnomad4 OTH

AF:

0.000473

AC:

0.000473037

AN:

0.000473037

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000673

Hom.:

Bravo

AF:

0.000423

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3Benign:2

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACAD9: PM2, PS3:Supporting -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 469 of the ACAD9 protein (p.Arg469Trp). This variant is present in population databases (rs139145143, gnomAD 0.07%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 20929961, 30025539; internal data). ClinVar contains an entry for this variant (Variation ID: 214007). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ACAD9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACAD9 function (PMID: 25721401). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 11, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acyl-CoA dehydrogenase 9 deficiency

Pathogenic:1Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 25, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 30, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

May 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACAD9 c.1405C>T (p.Arg469Trp) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0004 in 251318 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACAD9 causing Mitochondrial Complex I Deficiency, Nuclear Type 20 (0.0004 vs 0.0011), allowing no conclusion about variant significance. c.1405C>T has been observed in individual(s) affected with Mitochondrial Complex I Deficiency (Gerards_2011, Repp_2018, internal data). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed the variant to have mildly decreased activity (about 80% of normal activity; Schiff_2015). The following publications have been ascertained in the context of this evaluation (PMID: 20929961, 30025539, 25721401, NO_PMID). ClinVar contains an entry for this variant (Variation ID: 214007). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.020

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.88

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.32

MutationAssessor

Uncertain

2.4

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.23

MVP

0.92

MPC

0.47

ClinPred

0.21

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.099

gMVP

0.54

Mutation Taster

=31/69

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over