Genetic Variant ACAD8:p.Thr32Ile (chr11-134253695-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014384.3(ACAD8):c.95C>T(p.Thr32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T32N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ACAD8
NM_014384.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.665

Publications

0 publications found

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 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17274347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD8	NM_014384.3 link	c.95C>T	p.Thr32Ile	missense_variant	Exon 1 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.95C>T	p.Thr32Ile	missense_variant	Exon 1 of 11	1	NM_014384.3	ENSP00000281182.5		Q9UKU7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718534

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33170

American (AMR)

AF:

0.00

AC:

AN:

42996

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25732

East Asian (EAS)

AF:

0.00

AC:

AN:

38938

South Asian (SAS)

AF:

0.00

AC:

AN:

84178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105640

Other (OTH)

AF:

0.00

AC:

AN:

59724

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

7.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.60

T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.17

T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

0.69

N;N

PhyloP100

-0.67

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.71

N;N

REVEL

Benign

0.24

Sift

Benign

0.094

T;D

Sift4G

Benign

0.17

T;D

Polyphen

0.0010

B;.

Vest4

0.12

MutPred

0.38

Loss of disorder (P = 0.0655);Loss of disorder (P = 0.0655);

MVP

0.86

MPC

0.16

ClinPred

0.10

GERP RS

1.2

PromoterAI

-0.051

Neutral

(source)

Varity_R

0.11

gMVP

0.53

Mutation Taster

=91/9

polymorphism

(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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chr11-134253695-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over