11-134253842-G-C

Position:

• chr11-134253842-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.109+133G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 974,908 control chromosomes in the GnomAD database, including 652 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (124 hom., cov: 32)
  • Exomes 𝑓: 0.032 (528 hom.)
• Consequence: ACAD8 NM_014384.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.203

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 (BayesDel_noAF=-0.88).
• BP6: Variant 11-134253842-G-C is Benign according to our data. Variant chr11-134253842-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 673122.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 = 0.037 (5551/150156) while in subpopulation AFR AF= 0.0428 (1748/40800). AF 95% confidence interval is 0.0412. There are 124 homozygotes in gnomad4. There are 2653 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 124 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD8	NM_014384.3	c.109+133G>C		intron_variant		ENST00000281182.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD8	ENST00000281182.9	c.109+133G>C		intron_variant		1	NM_014384.3	P1

Frequencies

GnomAD3 genomes AF: 0.0370 AC: 5548 AN: 150046 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0429

Gnomad AMI AF: 0.00895

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.0281

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.00706

Gnomad FIN AF: 0.0424

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0292

GnomAD4 exome AF: 0.0323 AC: 26599 AN: 824752 Hom.: 528 AF XY: 0.0317 AC XY: 13497 AN XY: 425900

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.0000303

Gnomad4 SAS exome AF: 0.00622

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0379

Gnomad4 OTH exome AF: 0.0317

GnomAD4 genome AF: 0.0370 AC: 5551 AN: 150156 Hom.: 124 Cov.: 32 AF XY: 0.0362 AC XY: 2653 AN XY: 73314

Gnomad4 AFR AF: 0.0428

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.0281

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.00707

Gnomad4 FIN AF: 0.0424

Gnomad4 NFE AF: 0.0419

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0160 Hom.: 7

Bravo AF: 0.0348

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs71486997; hg19: chr11-134123736;