rs767041100

Positions:

• chr11-134253602-T-A
• chr11-134253602-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_014384.3(ACAD8):​c.2T>A​(p.Met1?) variant causes a start lost 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACAD8 NM_014384.3 start_lost
• Clinical Significance: Not reported in ClinVar
• 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 12 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 Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAD8	NM_014384.3	c.2T>A	p.Met1?	start_lost	1/11	ENST00000281182.9	NP_055199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9	c.2T>A	p.Met1?	start_lost	1/11	1	NM_014384.3	ENSP00000281182.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431426 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709928

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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 Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.40	D
PROVEAN	Benign	-0.56	N;N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.0	B;.
Vest4		0.62
MutPred		0.99		Loss of stability (P = 0.0141);Loss of stability (P = 0.0141);
MVP		0.97
ClinPred		1.0	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.91
gMVP		0.81

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;