chr3-128904079-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_014049.5(ACAD9):c.976G>A(p.Ala326Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0181 in 1,614,070 control chromosomes in the GnomAD database, including 411 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A326P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.017 ( 48 hom., cov: 33)

Exomes 𝑓: 0.018 ( 363 hom. )

Consequence

ACAD9
NM_014049.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 7.03

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

acyl-CoA dehydrogenase 9 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

ACAD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-128904079-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.009568185).

BP6

Variant 3-128904079-G-A is Benign according to our data. Variant chr3-128904079-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0172 (2615/152298) while in subpopulation NFE AF = 0.0251 (1704/68020). AF 95% confidence interval is 0.0241. There are 48 homozygotes in GnomAd4. There are 1288 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD9	NM_014049.5 link	c.976G>A	p.Ala326Thr	missense_variant	Exon 10 of 18	ENST00000308982.12	NP_054768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982.12 link	c.976G>A	p.Ala326Thr	missense_variant	Exon 10 of 18	1	NM_014049.5	ENSP00000312618.7

Frequencies

GnomAD3 genomes

AF:

0.0172

AC:

2617

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.0222

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0455

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0250

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0177

AC:

4446

AN:

251452

AF XY:

0.0182

show subpopulations

Gnomad AFR exome

AF:

0.00332

Gnomad AMR exome

AF:

0.00642

Gnomad ASJ exome

AF:

0.0255

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0453

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0256

GnomAD4 exome

AF:

0.0182

AC:

26626

AN:

1461772

Hom.:

363

Cov.:

AF XY:

0.0183

AC XY:

13297

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00281

AC:

AN:

33476

American (AMR)

AF:

0.00789

AC:

353

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0243

AC:

636

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39698

South Asian (SAS)

AF:

0.00489

AC:

422

AN:

86258

European-Finnish (FIN)

AF:

0.0456

AC:

2433

AN:

53412

Middle Eastern (MID)

AF:

0.0246

AC:

142

AN:

5768

European-Non Finnish (NFE)

AF:

0.0193

AC:

21417

AN:

1111910

Other (OTH)

AF:

0.0186

AC:

1125

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

1430

2859

4289

5718

7148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

656

1312

1968

2624

3280

<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:

0.0172

AC:

2615

AN:

152298

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1288

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41570

American (AMR)

AF:

0.0107

AC:

163

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00559

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0455

AC:

483

AN:

10606

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0251

AC:

1704

AN:

68020

Other (OTH)

AF:

0.0184

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

133

265

398

530

663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0198

Hom.:

126

Bravo

AF:

0.0131

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.0143

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0219

AC:

188

ExAC

AF:

0.0182

AC:

2213

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0238

EpiControl

AF:

0.0217

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 20, 2012

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Acyl-CoA dehydrogenase 9 deficiency

Benign:5

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mar 11, 2025

SIB Swiss Institute of Bioinformatics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as likely benign for Mitochondrial complex I deficiency due to ACAD9 deficiency, autosomal recessive. This variant is found in population databases (gnomAD v4.1.0) at a frequency greater than expected for the disorder (BS1) and is observed at homozygosity in 411 individuals in gnomAD v4.1.0 (BS2_supporting). -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0096

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.2

PhyloP100

7.0

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.24

MPC

0.71

ClinPred

0.012

GERP RS

5.5

Varity_R

0.71

gMVP

0.91

Mutation Taster

=81/19

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over