11-134253728-G-T

Variant names:

• chr11-134253728-G-T
• rs1466466553
• NM_014384.3:c.109+19G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014384.3(ACAD8):​c.109+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACAD8 NM_014384.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.354
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD8	NM_014384.3	c.109+19G>T		intron_variant	Intron 1 of 10	ENST00000281182.9	NP_055199.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9	c.109+19G>T		intron_variant	Intron 1 of 10	1	NM_014384.3	ENSP00000281182.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000567 AC: 1 AN: 176368 AF XY: 0.0000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422426 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 704576

African (AFR) AF: 0.00 AC: 0 AN: 32498

American (AMR) AF: 0.0000255 AC: 1 AN: 39156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25410

East Asian (EAS) AF: 0.00 AC: 0 AN: 37530

South Asian (SAS) AF: 0.00 AC: 0 AN: 81782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092888

Other (OTH) AF: 0.0000170 AC: 1 AN: 58924

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of isobutyryl-CoA dehydrogenase Uncertain:1

Aug 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 2182881). This variant has not been reported in the literature in individuals affected with ACAD8-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change falls in intron 1 of the ACAD8 gene. It does not directly change the encoded amino acid sequence of the ACAD8 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.3
DANN	Benign	0.48
PhyloP100		0.35
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.89		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1466466553; hg19: chr11-134123622;