rs139145143

Positions:

• chr3-128909019-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: ACAD9 NM_014049.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 B:2
• Conservation: PhyloP100: 0.933

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 Likely_benign. Variant got -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: {Likely_pathogenic=2, Uncertain_significance=5}.
• 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/exons	MANE	Protein	UniProt
ACAD9	NM_014049.5	c.1405C>T	p.Arg469Trp	missense_variant	14/18	ENST00000308982.12	NP_054768.2
ACAD9	NM_001410805.1	c.1036C>T	p.Arg346Trp	missense_variant	13/17		NP_001397734.1
ACAD9	XM_024453484.2	c.1036C>T	p.Arg346Trp	missense_variant	14/18		XP_024309252.1
ACAD9	NR_033426.2	n.1653C>T		non_coding_transcript_exon_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982.12	c.1405C>T	p.Arg469Trp	missense_variant	14/18	1	NM_014049.5	ENSP00000312618	P1

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152238 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000398 AC: 100 AN: 251318 Hom.: 0 AF XY: 0.000434 AC XY: 59 AN XY: 135896

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 SAS exome AF: 0.0000653

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.: 2 Cov.: 35 AF XY: 0.000738 AC XY: 537 AN XY: 727214

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.000972

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152356 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74492

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000700 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ACAD9: PM2, PS3:Supporting -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 214007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Acyl-CoA dehydrogenase 9 deficiency Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 04, 2018	The ACAD9 c.1405C>T (p.Arg469Trp) missense variant has been reported in one study in which it was identified in a compound heterozygous state with a second missense variant in one individual with mitochondrial complex I deficiency (Gerards et al. 2011). A muscle biopsy from the affected individual indicated a 91% reduction in mitochondrial complex 1 activity compared to control (Scholte et al. 1995). The p.Arg469Trp variant was absent from 233 controls and is reported at a frequency of 0.000744 in the European (non-Finnish) population of the Genome Aggregation Database. Recombinant Arg469Trp ACAD9 protein, derived from a bacterial expression system was stable and showed a mildly decreased enzyme activity compared to wild type (Schiff et al. 2015). Based on the evidence, the p.Arg469Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for ACAD9 deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 30, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 13, 2023

Variant summary: ACAD9 c.1405C>T (p.Arg469Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 251318 control chromosomes. This frequency is not significantly higher than expected 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 reported in the literature in individuals affected with Mitochondrial Complex I Deficiency, Nuclear Type 20. These reports do not provide unequivocal conclusions about association of the variant with Mitochondrial Complex I Deficiency, Nuclear Type 20. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant effect results in about 80% of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS n=5, likely pathogenic n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.23
MVP		0.92
MPC		0.47
ClinPred		0.21	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.54

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

Other links and lift over

dbSNP: rs139145143; hg19: chr3-128627862;