rs200620279

Positions:

chr11-134261756-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

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

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.87

Variant links:

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]

ACAD8 links:

ACAD8 (HGNC:):

ACAD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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, Pathogenic=2, Likely_pathogenic=4}. Variant chr11-134261756-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAD8	NM_014384.3 linkuse as main transcript	c.958G>A	p.Ala320Thr	missense_variant	9/11	ENST00000281182.9	NP_055199.1	Q9UKU7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9 linkuse as main transcript	c.958G>A	p.Ala320Thr	missense_variant	9/11	1	NM_014384.3	ENSP00000281182.5		Q9UKU7-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

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:

AN:

250968

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

135676

show subpopulations

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.:

Cov.:

AF XY:

0.000254

AC XY:

185

AN XY:

727116

show subpopulations

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:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000296

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 08, 2020	- -
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	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	Labcorp Genetics (formerly Invitae), Labcorp	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. -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 29, 2024	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 (PMID: 16857760); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16857760, 17304052, 33432785, 34426522, 32778825, 24635911, Lina2023[Article]) -

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

BayesDel_noAF

Pathogenic

0.59

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

H;.

PrimateAI

Uncertain

0.53

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

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

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