11-134253602-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_014384.3(ACAD8):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000505 in 1,583,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: ACAD8 NM_014384.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.589

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_014384.3 (ACAD8) was described as [Likely_pathogenic] in ClinVar as 430159
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-134253602-T-C is Pathogenic according to our data. Variant chr11-134253602-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 566782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD8	NM_014384.3	c.2T>C	p.Met1?	start_lost	1/11	ENST00000281182.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD8	ENST00000281182.9	c.2T>C	p.Met1?	start_lost	1/11	1	NM_014384.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000311 AC: 6 AN: 193186 Hom.: 0 AF XY: 0.0000188 AC XY: 2 AN XY: 106136

Gnomad AFR exome AF: 0.0000956

Gnomad AMR exome AF: 0.000166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1431426 Hom.: 0 Cov.: 31 AF XY: 0.00000282 AC XY: 2 AN XY: 709928

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.000122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000260 AC: 3

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 20, 2022	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. ClinVar contains an entry for this variant (Variation ID: 566782). Disruption of the initiator codon has been observed in individual(s) with isobutyryl-CoA dehydrogenase deficiency (PMID: 17924841, 24635911, 30626930). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs767041100, gnomAD 0.02%). This sequence change affects the initiator methionine of the ACAD8 mRNA. The next in-frame methionine is located at codon 39. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	19
Dann	Benign	0.92
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.53	N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.039	B;.
Vest4		0.66
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0116);Gain of catalytic residue at M1 (P = 0.0116);
MVP		0.97
ClinPred		0.99	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.87
gMVP		0.71

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: rs767041100; hg19: chr11-134123496;