rs121908421

Positions:

• chr11-134261300-C-A
• chr11-134261300-C-G
• chr11-134261300-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The ENST00000281182.9(ACAD8):​c.867C>A​(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 Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACAD8 ENST00000281182.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0690

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 36) in uniprot entity ACAD8_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in ENST00000281182.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 11-134261300-C-A is Pathogenic according to our data. Variant chr11-134261300-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5358.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-134261300-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAD8	NM_014384.3	c.867C>A	p.His289Gln	missense_variant	8/11	ENST00000281182.9	NP_055199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9	c.867C>A	p.His289Gln	missense_variant	8/11	1	NM_014384.3	ENSP00000281182	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	2.0
DANN	Benign	0.65
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.9	N;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	1.9	N;N
REVEL	Uncertain	0.52
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
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: rs121908421; hg19: chr11-134131194;