rs115532916

chr3-128904079-G-Achr3-128904079-G-Cchr3-128904079-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM5 BP4_Strong BP6 BS1 BS2

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 Conflicting classifications of pathogenicity (no stars). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 7.03

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 Benign. Variant got -11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128904079-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136253.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=1, Uncertain_significance=1}. Variant chr3-128904079-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 48 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD9	NM_014049.5	c.976G>A	p.Ala326Thr	missense_variant	10/18	ENST00000308982.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD9	ENST00000308982.12	c.976G>A	p.Ala326Thr	missense_variant	10/18	1	NM_014049.5	P1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2617 AN: 152178 Hom.: 48 Cov.: 33

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

GnomAD3 exomes AF: 0.0177 AC: 4446 AN: 251452 Hom.: 75 AF XY: 0.0182 AC XY: 2478 AN XY: 135918

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 SAS exome AF: 0.00500

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.: 31 AF XY: 0.0183 AC XY: 13297 AN XY: 727184

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00789

Gnomad4 ASJ exome AF: 0.0243

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00489

Gnomad4 FIN exome AF: 0.0456

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0172 AC: 2615 AN: 152298 Hom.: 48 Cov.: 33 AF XY: 0.0173 AC XY: 1288 AN XY: 74470

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.0455

Gnomad4 NFE AF: 0.0251

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0210 Hom.: 97

Bravo AF: 0.0131

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.0143 AC: 55

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0219 AC: 188

ExAC AF: 0.0182 AC: 2213

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0238

EpiControl AF: 0.0217

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acyl-CoA dehydrogenase 9 deficiency Uncertain:1 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as of Uncertain Significance - Conflicting Evidence, for Mitochondrial complex I deficiency due to ACAD9 deficiency, autosomal recessive. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2012	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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 31, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.24
MPC		0.71
ClinPred		0.012	T
GERP RS		5.5
Varity_R		0.71
gMVP		0.91

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: rs115532916; hg19: chr3-128622922; COSMIC: COSV58307871; COSMIC: COSV58307871;