Genetic Variant NM_014384.3:c.109+133G>C (chr11-134253842-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.203

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ACAD8	NM_014384.3 link	c.109+133G>C		intron_variant	Intron 1 of 10	ENST00000281182.9	NP_055199.1	Q9UKU7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD8	ENST00000281182.9 link	c.109+133G>C		intron_variant	Intron 1 of 10	1	NM_014384.3	ENSP00000281182.5		Q9UKU7-1

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5548

AN:

150046

Hom.:

124

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0362

AC XY:

2653

AN XY:

73314

show subpopulations

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.:

Bravo

AF:

0.0348

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over