rs60400822

Variant names:

• chr17-7221515-CCA-C
• rs60400822
• NM_000018.4:c.478-22_478-21delCA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.478-22_478-21del variant in ACADVL is an intronic variant which occurs in intron 6. The highest population minor allele frequency in gnomAD v2.1.1 is 0.2253 in the African population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from in silico splicing predictors (SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337734/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.065 (1057 hom., cov: 31)
  • Exomes 𝑓: 0.0078 (1000 hom.)
• Consequence: ACADVL NM_000018.4 intron
• Clinical Significance: Benign reviewed by expert panel B:5
• Conservation: PhyloP100: -0.514

Genes affected

ACADVL (HGNC:92): (acyl-CoA dehydrogenase very long chain) The protein encoded by this gene is targeted to the inner mitochondrial membrane where it catalyzes the first step of the mitochondrial fatty acid beta-oxidation pathway. This acyl-Coenzyme A dehydrogenase is specific to long-chain and very-long-chain fatty acids. A deficiency in this gene product reduces myocardial fatty acid beta-oxidation and is associated with cardiomyopathy. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.478-22_478-21delCA		intron_variant	Intron 6 of 19	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.478-22_478-21delCA		intron_variant	Intron 6 of 19	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9861 AN: 152026 Hom.: 1049 Cov.: 31

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.0464

GnomAD3 exomes AF: 0.0181 AC: 4552 AN: 251378 Hom.: 399 AF XY: 0.0136 AC XY: 1854 AN XY: 135892

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.0132

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00778 AC: 11379 AN: 1461780 Hom.: 1000 AF XY: 0.00692 AC XY: 5032 AN XY: 727194

Gnomad4 AFR exome AF: 0.231

Gnomad4 AMR exome AF: 0.0149

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0651 AC: 9900 AN: 152144 Hom.: 1057 Cov.: 31 AF XY: 0.0624 AC XY: 4642 AN XY: 74378

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.0459

Alfa AF: 0.0283 Hom.: 5

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Benign:3

Nov 01, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000018.3:c.478-22_478-21delCA (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7221516_7221517delCA] variant in ACADVL gene is interpretated to be Benign based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: BS1, BS2 -

Sep 22, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.478-22_478-21del variant in ACADVL is an intronic variant which occurs in intron 6. The highest population minor allele frequency in gnomAD v2.1.1 is 0.2253 in the African population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). The results from in silico splicing predictors (SpliceAI) support that this variant does not affect splicing (BP4). In summary, this variant meets the criteria to be classified as benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BA1, BP4. -

Nov 13, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs60400822; hg19: chr17-7124834;