rs200620279

chr11-134261756-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_014384.3(ACAD8):c.958G>A(p.Ala320Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,613,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (1 hom.)
• Consequence: ACAD8 NM_014384.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 9.87

Genes affected

ACAD8 (HGNC:87): (acyl-CoA dehydrogenase family member 8) This gene encodes a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. The encoded protein is a mitochondrial enzyme that functions in catabolism of the branched-chain amino acid valine. Defects in this gene are the cause of isobutyryl-CoA dehydrogenase deficiency.[provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 28) in uniprot entity ACAD8_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_014384.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 11-134261756-G-A is Pathogenic according to our data. Variant chr11-134261756-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372297.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=4, Pathogenic=2}. Variant chr11-134261756-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD8	NM_014384.3	c.958G>A	p.Ala320Thr	missense_variant	9/11	ENST00000281182.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD8	ENST00000281182.9	c.958G>A	p.Ala320Thr	missense_variant	9/11	1	NM_014384.3	P1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000367 AC: 92 AN: 250968 Hom.: 0 AF XY: 0.000398 AC XY: 54 AN XY: 135676

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00177

Gnomad NFE exome AF: 0.000361

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1461656 Hom.: 1 Cov.: 31 AF XY: 0.000254 AC XY: 185 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00175

Gnomad4 NFE exome AF: 0.000187

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74468

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000296 AC: 36

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 18, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 320 of the ACAD8 protein (p.Ala320Thr). This variant is present in population databases (rs200620279, gnomAD 0.2%). This missense change has been observed in individual(s) with isobutyryl-CoA dehydrogenase deficiency (PMID: 16857760, 17304052, 32778825; Invitae). This variant is also known as A298T. ClinVar contains an entry for this variant (Variation ID: 372297). 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 expected to disrupt ACAD8 protein function. Experimental studies have shown that this missense change affects ACAD8 function (PMID: 16857760). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 05, 2018	The ACAD8 c.958G>A (p.Ala320Thr) missense variant has been reported in a compound heterozygous state in two individuals with isobutyryl-CoA dehydrogenase deficiency who were identified by elevated C4-carnitine levels through newborn screening (Pedersen et al. 2006; Oglesbee et al. 2007). This variant was absent from 415 controls but is reported at a frequency of 0.001563 in the European (Finnish) population of the Genome Aggregation Database. When overexpressed in Chang cells, the p.Ala320Thr variant displayed approximately 20% residual enzyme activity. Experiments in isolated mitochondria also showed the variant reduced isobutyryl-CoA dehydrogenase tetramer formation, suggesting disruption of protein folding (Pedersen et al. 2006). Based on the collective evidence, the p.Ala320Thr variant is classified as likely pathogenic for isobutyryl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 08, 2020	- -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2023	Expression studies found that A320T is associated with approximately 20% isobutyryl-CoA dehydrogenase enzyme activity compared to wild-type and that it affects proper isobutyryl-CoA dehydrogenase protein folding (Pedersen et al., 2006); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33432785, 16857760, 17304052, 34426522, 32778825, 24635911, Lina2023[Article]) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -

ACAD8-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

The ACAD8 c.958G>A variant is predicted to result in the amino acid substitution p.Ala320Thr. This variant has been reported in the compound heterozygous state in two presumably unrelated individuals with isobutyryl-CoA dehydrogenase deficiency (Table 1, Pedersen et al. 2006. PubMed ID: 16857760; Table 1, Oglesbee et al. 2007. PubMed ID: 17304052). It has been reported in an additional individual with an inborn error of metabolism, but no clinical data was provided (Table S5, Adhikari et al. 2020. PubMed ID: 32778825). It has been reported in the compound heterozygous state in an additional individual with elevated C4-acylcarnitine on newborn screening (Internal Data, PreventionGenetics). This variant has been demonstrated to retain approximately 20% of residual enzymatic activity compared to wild type (Figure 2, Pedersen et al. 2006. PubMed ID: 16857760). This variant is reported in 0.17% of alleles in individuals of European (Finnish) descent in gnomAD (https://gnomad.broadinstitute.org/variant/11-134131650-G-A. This variant is interpreted as likely pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 04, 2021

The c.958G>A (p.A320T) alteration is located in exon 9 (coding exon 9) of the ACAD8 gene. This alteration results from a G to A substitution at nucleotide position 958, causing the alanine (A) at amino acid position 320 to be replaced by a threonine (T). Based on data from the Genome Aggregation Database (gnomAD) database, the ACAD8 c.958G>A alteration was observed in 0.03% (98/282364) of total alleles studied, with a frequency of 0.17% (43/24928) in the European (Finnish) subpopulation. This alteration has been reported in the compound heterozygous state with other ACAD8 variants in two patients with isobutyryl-CoA dehydrogenase deficiency identified by elevated C4-carnitine on newborn screening (Oglesbee, 2007; Pedersen, 2006). One patient was described as having an unremarkable clinical presentation, and the clinical status of the other patient was not determined (Oglesbee, 2007; Pedersen, 2006). This amino acid position is well conserved in available vertebrate species. The p.A320T alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.99
MVP		1.0
MPC		0.63
ClinPred		0.72	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200620279; hg19: chr11-134131650;