chr11-134256374-A-G

Variant names:

• chr11-134256374-A-G
• rs35141157
• NM_014384.3:c.110-174A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_014384.3(ACAD8):​c.110-174A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 152,280 control chromosomes in the GnomAD database, including 125 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 (125 hom., cov: 33)
• Consequence: ACAD8 NM_014384.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0620
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-134256374-A-G is Benign according to our data. Variant chr11-134256374-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 673123.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0372 (5670/152280) while in subpopulation AFR AF = 0.0437 (1815/41556). AF 95% confidence interval is 0.042. There are 125 homozygotes in GnomAd4. There are 2715 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 125 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	NM_014384.3	MANE Select	c.110-174A>G		intron	N/A	NP_055199.1	Q9UKU7-1
	ACAD8	NM_001441136.1		c.110-174A>G		intron	N/A	NP_001428065.1
	ACAD8	NM_001441138.1		c.-15-174A>G		intron	N/A	NP_001428067.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD8	ENST00000281182.9	TSL:1 MANE Select	c.110-174A>G		intron	N/A	ENSP00000281182.5	Q9UKU7-1
	ACAD8	ENST00000527082.5	TSL:1	n.134-174A>G		intron	N/A
	ACAD8	ENST00000869565.1		c.110-174A>G		intron	N/A	ENSP00000539624.1

Frequencies

GnomAD3 genomes AF: 0.0372 AC: 5666 AN: 152162 Hom.: 125 Cov.: 33

Gnomad AFR AF: 0.0437

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0227

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.0422

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0301

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0372 AC: 5670 AN: 152280 Hom.: 125 Cov.: 33 AF XY: 0.0365 AC XY: 2715 AN XY: 74466

African (AFR) AF: 0.0437 AC: 1815 AN: 41556

American (AMR) AF: 0.0227 AC: 347 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00705 AC: 34 AN: 4824

European-Finnish (FIN) AF: 0.0422 AC: 448 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0419 AC: 2853 AN: 68010

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0395 Hom.: 171

Bravo AF: 0.0352

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.4
DANN	Benign	0.49
PhyloP100		0.062
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs35141157; hg19: chr11-134126268;