Variant 11-134253603-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_014384.3(ACAD8):c.3G>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000978 in 1,431,656 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: not found (cov: 32)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

ACAD8
NM_014384.3 start_lost

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.12

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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;

PP5

Variant 11-134253603-G-C is Pathogenic according to our data. Variant chr11-134253603-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2047520.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACAD8	NM_014384.3 link	c.3G>C	p.Met1?	start_lost	1/11	ENST00000281182.9	NP_055199.1	Q9UKU7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9 link	c.3G>C	p.Met1?	start_lost	1/11	1	NM_014384.3	ENSP00000281182.5		Q9UKU7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000207

AC:

AN:

193620

Hom.:

AF XY:

0.0000282

AC XY:

AN XY:

106416

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000113

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000120

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000978

AC:

AN:

1431656

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

710054

show subpopulations

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:

0.0000604

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000819

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000174

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2022

This sequence change affects the initiator methionine of the ACAD8 mRNA. The next in-frame methionine is located at codon 39. This variant is present in population databases (rs751940610, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with Isobutyryl-CoA dehydrogenase deficiency (PMID: 17924841, 24635911; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.35

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.56

PROVEAN

Benign

-0.58

N;N

REVEL

Uncertain

0.49

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.020

B;.

Vest4

0.77

MutPred

0.99

Gain of catalytic residue at M1 (P = 0.0657);Gain of catalytic residue at M1 (P = 0.0657);

MVP

0.94

ClinPred

1.0

GERP RS

5.6

Varity_R

0.95

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over