chr11-134253842-G-C

Variant names:

• chr11-134253842-G-C
• rs71486997
• NM_014384.3:c.109+133G>C

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 124 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD8	NM_014384.3	c.109+133G>C		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+133G>C		intron_variant	Intron 1 of 10	1	NM_014384.3	ENSP00000281182.5

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

African (AFR) AF: 0.0389 AC: 808 AN: 20760

American (AMR) AF: 0.0161 AC: 555 AN: 34508

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 564 AN: 21240

East Asian (EAS) AF: 0.0000303 AC: 1 AN: 33018

South Asian (SAS) AF: 0.00622 AC: 418 AN: 67194

European-Finnish (FIN) AF: 0.0387 AC: 1279 AN: 33026

Middle Eastern (MID) AF: 0.0109 AC: 46 AN: 4238

European-Non Finnish (NFE) AF: 0.0379 AC: 21678 AN: 571362

Other (OTH) AF: 0.0317 AC: 1250 AN: 39406

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

African (AFR) AF: 0.0428 AC: 1748 AN: 40800

American (AMR) AF: 0.0224 AC: 339 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 97 AN: 3448

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5080

South Asian (SAS) AF: 0.00707 AC: 33 AN: 4670

European-Finnish (FIN) AF: 0.0424 AC: 441 AN: 10412

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 290

European-Non Finnish (NFE) AF: 0.0419 AC: 2821 AN: 67354

Other (OTH) AF: 0.0289 AC: 60 AN: 2078

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.4
DANN	Benign	0.43
PhyloP100		-0.20
PromoterAI		-0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs71486997; hg19: chr11-134123736;