11-134253620-G-C

Position:

• chr11-134253620-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014384.3(ACAD8):​c.20G>C​(p.Arg7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,579,502 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (24 hom.)
• Consequence: ACAD8 NM_014384.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.314

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023905635).
• BP6: Variant 11-134253620-G-C is Benign according to our data. Variant chr11-134253620-G-C is described in ClinVar as [Benign]. Clinvar id is 95584.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.01 (1529/152300) while in subpopulation AFR AF= 0.0346 (1437/41576). AF 95% confidence interval is 0.0331. There are 18 homozygotes in gnomad4. There are 703 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD8	NM_014384.3	c.20G>C	p.Arg7Pro	missense_variant	1/11	ENST00000281182.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD8	ENST00000281182.9	c.20G>C	p.Arg7Pro	missense_variant	1/11	1	NM_014384.3	P1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1527 AN: 152182 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00229 AC: 413 AN: 180046 Hom.: 5 AF XY: 0.00163 AC XY: 162 AN XY: 99446

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000776

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000258

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00106 AC: 1514 AN: 1427202 Hom.: 24 Cov.: 31 AF XY: 0.000931 AC XY: 659 AN XY: 707810

Gnomad4 AFR exome AF: 0.0350

Gnomad4 AMR exome AF: 0.00208

Gnomad4 ASJ exome AF: 0.0000392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000727

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000938

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.0100 AC: 1529 AN: 152300 Hom.: 18 Cov.: 33 AF XY: 0.00944 AC XY: 703 AN XY: 74482

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000829 Hom.: 2

Bravo AF: 0.0113

ESP6500AA AF: 0.0266 AC: 107

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.00243 AC: 283

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 08, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	7.1
DANN	Benign	0.94
DEOGEN2	Benign	0.30	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Uncertain	0.058	D
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.24
Sift	Benign	0.23	T;D
Sift4G	Benign	0.21	T;T
Polyphen		0.0	B;.
Vest4		0.29
MVP		0.81
MPC		0.21
ClinPred		0.0069	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.80

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: rs35181923; hg19: chr11-134123514;