rs77368661

Variant names:

• chr11-134261186-T-C
• rs77368661
• NM_014384.3:c.841+7T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014384.3(ACAD8):​c.841+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00855 in 1,613,692 control chromosomes in the GnomAD database, including 1,014 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (529 hom., cov: 33)
  • Exomes 𝑓: 0.0047 (485 hom.)
• Consequence: ACAD8 NM_014384.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001230
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.07
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 11-134261186-T-C is Benign according to our data. Variant chr11-134261186-T-C is described in ClinVar as Benign. ClinVar VariationId is 303680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

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.841+7T>C		splice_region intron	N/A	NP_055199.1	Q9UKU7-1
	ACAD8	NM_001441136.1		c.841+7T>C		splice_region intron	N/A	NP_001428065.1
	ACAD8	NM_001441138.1		c.547+7T>C		splice_region 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.841+7T>C		splice_region intron	N/A	ENSP00000281182.5	Q9UKU7-1
	ACAD8	ENST00000531338.5	TSL:1	n.697+7T>C		splice_region intron	N/A
	ACAD8	ENST00000869565.1		c.1105+7T>C		splice_region intron	N/A	ENSP00000539624.1

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6927 AN: 152140 Hom.: 529 Cov.: 33

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0120 AC: 2988 AN: 249682 AF XY: 0.00850

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.00793

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00691

GnomAD4 exome AF: 0.00469 AC: 6849 AN: 1461434 Hom.: 485 Cov.: 31 AF XY: 0.00395 AC XY: 2868 AN XY: 726988

African (AFR) AF: 0.165 AC: 5527 AN: 33480

American (AMR) AF: 0.00999 AC: 446 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.000175 AC: 195 AN: 1111880

Other (OTH) AF: 0.0101 AC: 611 AN: 60372

GnomAD4 genome AF: 0.0456 AC: 6945 AN: 152258 Hom.: 529 Cov.: 33 AF XY: 0.0431 AC XY: 3210 AN XY: 74460

African (AFR) AF: 0.158 AC: 6549 AN: 41524

American (AMR) AF: 0.0198 AC: 303 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68010

Other (OTH) AF: 0.0289 AC: 61 AN: 2112

Alfa AF: 0.0235 Hom.: 141

Bravo AF: 0.0532

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000655

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Deficiency of isobutyryl-CoA dehydrogenase (2)
-	-	1	ACAD8-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.6
DANN	Benign	0.49
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.0040
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

Other links and lift over

dbSNP: rs77368661; hg19: chr11-134131080;