11-134261300-C-G

Variant names:

• chr11-134261300-C-G
• rs121908421
• NM_014384.3:c.867C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM2 PP3

The NM_014384.3(ACAD8):​c.867C>G​(p.His289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H289H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAD8 NM_014384.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0690
• Publications: 2 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS1: Transcript NM_014384.3 (ACAD8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	NM_014384.3	MANE Select	c.867C>G	p.His289Gln	missense	Exon 8 of 11	NP_055199.1
	ACAD8	NM_001441136.1		c.867C>G	p.His289Gln	missense	Exon 8 of 11	NP_001428065.1
	ACAD8	NM_001441138.1		c.573C>G	p.His191Gln	missense	Exon 7 of 10	NP_001428067.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	ENST00000281182.9	TSL:1 MANE Select	c.867C>G	p.His289Gln	missense	Exon 8 of 11	ENSP00000281182.5
	ACAD8	ENST00000531338.5	TSL:1	n.723C>G		non_coding_transcript_exon	Exon 7 of 10
	ACAD8	ENST00000374752.6	TSL:2	c.486C>G	p.His162Gln	missense	Exon 5 of 8	ENSP00000363884.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase Uncertain:1

Aug 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	3.2
DANN	Benign	0.65
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.069	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.9	N
PhyloP100		0.069
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	1.9	N
REVEL	Uncertain	0.52
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.77
MutPred		0.85		Gain of relative solvent accessibility (P = 0.2363)
MVP		0.93
MPC		0.15
ClinPred		0.22	T
GERP RS		0.068
Varity_R		0.53
gMVP		0.71
Mutation Taster		=3/97	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121908421; hg19: chr11-134131194;