rs200620279

Variant names:

• chr11-134261756-G-A
• rs200620279
• NM_014384.3:c.958G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV000490392: 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)" and additional evidence is available in ClinVar.

• 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:9 U:2 O:1
• Conservation: PhyloP100: 9.87
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• isobutyryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000490392: 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); SCV000820709: Experimental studies have shown that this missense change affects ACAD8 function (PMID: 16857760).; SCV000914498: 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).; SCV004112828: 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).
• 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 VariationId is 372297.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	NM_014384.3	MANE Select	c.958G>A	p.Ala320Thr	missense	Exon 9 of 11	NP_055199.1	Q9UKU7-1
	ACAD8	NM_001441136.1		c.958G>A	p.Ala320Thr	missense	Exon 9 of 11	NP_001428065.1
	ACAD8	NM_001441138.1		c.664G>A	p.Ala222Thr	missense	Exon 8 of 10	NP_001428067.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	ENST00000281182.9	TSL:1 MANE Select	c.958G>A	p.Ala320Thr	missense	Exon 9 of 11	ENSP00000281182.5	Q9UKU7-1
	ACAD8	ENST00000531338.5	TSL:1	n.814G>A		non_coding_transcript_exon	Exon 8 of 10
	ACAD8	ENST00000869565.1		c.1222G>A	p.Ala408Thr	missense	Exon 10 of 12	ENSP00000539624.1

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

GnomAD2 exomes AF: 0.000367 AC: 92 AN: 250968 AF XY: 0.000398

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86254

European-Finnish (FIN) AF: 0.00175 AC: 93 AN: 53196

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000187 AC: 208 AN: 1112010

Other (OTH) AF: 0.000281 AC: 17 AN: 60392

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

African (AFR) AF: 0.00 AC: 0 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000299 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	-	-	Deficiency of isobutyryl-CoA dehydrogenase (8)
1	1	-	not provided (2)
1	-	-	ACAD8-related disorder (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200620279; hg19: chr11-134131650;