rs113488591

Positions:

chr11-134259029-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014384.3(ACAD8):c.512C>G(p.Ser171Cys) variant causes a missense change. The variant allele was found at a frequency of 0.021 in 1,613,960 control chromosomes in the GnomAD database, including 407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 20 hom., cov: 32)

Exomes 𝑓: 0.022 ( 387 hom. )

Consequence

ACAD8
NM_014384.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012948006).

BP6

Variant 11-134259029-C-G is Benign according to our data. Variant chr11-134259029-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 95589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-134259029-C-G is described in Lovd as [Likely_pathogenic]. Variant chr11-134259029-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0153 (2323/152298) while in subpopulation NFE AF= 0.0236 (1606/68036). AF 95% confidence interval is 0.0226. There are 20 homozygotes in gnomad4. There are 1079 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD8	NM_014384.3 linkuse as main transcript	c.512C>G	p.Ser171Cys	missense_variant	5/11	ENST00000281182.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD8	ENST00000281182.9 linkuse as main transcript	c.512C>G	p.Ser171Cys	missense_variant	5/11	1	NM_014384.3	P1	Q9UKU7-1

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2323

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00471

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0236

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.0143

AC:

3590

AN:

251482

Hom.:

AF XY:

0.0139

AC XY:

1896

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00461

Gnomad AMR exome

AF:

0.0103

Gnomad ASJ exome

AF:

0.00506

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.0161

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0216

AC:

31539

AN:

1461662

Hom.:

387

Cov.:

AF XY:

0.0210

AC XY:

15273

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00373

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.00513

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.0160

Gnomad4 NFE exome

AF:

0.0256

Gnomad4 OTH exome

AF:

0.0210

GnomAD4 genome

AF:

0.0153

AC:

2323

AN:

152298

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1079

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00469

Gnomad4 AMR

AF:

0.0212

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0236

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0159

TwinsUK

AF:

0.0245

AC:

ALSPAC

AF:

0.0272

AC:

105

ESP6500AA

AF:

0.00863

AC:

ESP6500EA

AF:

0.0221

AC:

190

ExAC

AF:

0.0143

AC:

1740

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0220

EpiControl

AF:

0.0223

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ACAD8: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2018	This variant is associated with the following publications: (PMID: 22995991, 17304052, 24635911, 27535533, 30626930) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Deficiency of isobutyryl-CoA dehydrogenase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Ser171Cys variant in ACAD8 has been reported in the compound heterozygous state in an individual with isobutyryl-CoA dehydrogenase deficiency (PMID: 17304052), but has been classified as benign for autosomal recessive isobutyryl-CoA dehydrogenase deficiency because it was identified in >2% of European (non-Finnish) chromosomes and 20 homozygotes by ExAC (http://gnomad.broadinstitute.org/), and less than 5 affected individuals have ever been reported. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.013

T;T

MetaSVM

Uncertain

0.69

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.5

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.43

MPC

0.25

ClinPred

0.034

GERP RS

4.8

Varity_R

0.96

gMVP

0.69

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