rs113488591

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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

Publications

20 publications found

Variant links:

COSMIC-nc: COSV107261969

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)

ACAD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD8	NM_014384.3 link	c.512C>G	p.Ser171Cys	missense_variant	Exon 5 of 11	ENST00000281182.9	NP_055199.1	Q9UKU7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9 link	c.512C>G	p.Ser171Cys	missense_variant	Exon 5 of 11	1	NM_014384.3	ENSP00000281182.5		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

GnomAD2 exomes

AF:

0.0143

AC:

3590

AN:

251482

AF XY:

0.0139

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 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

African (AFR)

AF:

0.00373

AC:

125

AN:

33480

American (AMR)

AF:

0.0110

AC:

494

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00513

AC:

134

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00155

AC:

134

AN:

86254

European-Finnish (FIN)

AF:

0.0160

AC:

852

AN:

53416

Middle Eastern (MID)

AF:

0.0149

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0256

AC:

28447

AN:

1111796

Other (OTH)

AF:

0.0210

AC:

1267

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1636

3272

4909

6545

8181

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0153

AC:

2323

AN:

152298

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

1079

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00469

AC:

195

AN:

41550

American (AMR)

AF:

0.0212

AC:

325

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00490

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0122

AC:

130

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0236

AC:

1606

AN:

68036

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

122

244

365

487

609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACAD8: BS1, BS2 -

Aug 27, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22995991, 17304052, 24635911, 27535533, 30626930) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Deficiency of isobutyryl-CoA dehydrogenase

Benign:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

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. -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Apr 12, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

5.8

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

Mutation Taster

=54/46

polymorphism (auto)

(source)

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

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rs113488591

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over