rs1064793430

Variant names:

• chr11-134253645-CCTGCCCG-C
• rs1064793430
• NM_014384.3:c.46_52delCTGCCCG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014384.3(ACAD8):​c.46_52delCTGCCCG​(p.Leu16AlafsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAD8 NM_014384.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.60
• Publications: 0 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: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 33 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-134253645-CCTGCCCG-C is Pathogenic according to our data. Variant chr11-134253645-CCTGCCCG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 418783.Status of the report is criteria_provided_single_submitter, 1 stars.

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.46_52delCTGCCCG	p.Leu16AlafsTer14	frameshift	Exon 1 of 11	NP_055199.1	Q9UKU7-1
	ACAD8	NM_001441136.1		c.46_52delCTGCCCG	p.Leu16AlafsTer14	frameshift	Exon 1 of 11	NP_001428065.1
	ACAD8	NM_001441137.1		c.46_52delCTGCCCG	p.Leu16AlafsTer14	frameshift	Exon 1 of 7	NP_001428066.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	ENST00000281182.9	TSL:1 MANE Select	c.46_52delCTGCCCG	p.Leu16AlafsTer14	frameshift	Exon 1 of 11	ENSP00000281182.5	Q9UKU7-1
	ACAD8	ENST00000527082.5	TSL:1	n.70_76delCTGCCCG		non_coding_transcript_exon	Exon 1 of 4
	ACAD8	ENST00000869565.1		c.46_52delCTGCCCG	p.Leu16AlafsTer14	frameshift	Exon 1 of 12	ENSP00000539624.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=18/182	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064793430; hg19: chr11-134123539;