rs17671352

Variant names:

• chr17-7224399-T-C
• rs17671352
• NM_000018.4:c.1605+6T>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

This summary comes from the ClinGen Evidence Repository: The c.1605+6T>C variant in ACADVL is an intronic variant which occurs in intron 16. The highest population minor allele frequency in gnomAD v2.1.1 is 0.66 in European Finnish 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 ExpertPanel: BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA274404/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.57 (25315 hom., cov: 31)
  • Exomes 𝑓: 0.62 (279411 hom.)
• Consequence: ACADVL NM_000018.4 splice_region, intron
• Scores: Splicing: ADA: 0.007159
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -0.253

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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• 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.1605+6T>C		splice_region_variant, intron_variant	Intron 16 of 19	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1605+6T>C		splice_region_variant, intron_variant	Intron 16 of 19	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes AF: 0.569 AC: 86437 AN: 151808 Hom.: 25290 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.603

GnomAD3 exomes AF: 0.598 AC: 149132 AN: 249274 Hom.: 45629 AF XY: 0.610 AC XY: 82392 AN XY: 135080

Gnomad AFR exome AF: 0.429

Gnomad AMR exome AF: 0.492

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.483

Gnomad SAS exome AF: 0.662

Gnomad FIN exome AF: 0.666

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.616 AC: 899884 AN: 1461136 Hom.: 279411 Cov.: 71 AF XY: 0.620 AC XY: 450287 AN XY: 726846

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.598

Gnomad4 EAS exome AF: 0.459

Gnomad4 SAS exome AF: 0.659

Gnomad4 FIN exome AF: 0.659

Gnomad4 NFE exome AF: 0.627

Gnomad4 OTH exome AF: 0.601

GnomAD4 genome AF: 0.569 AC: 86505 AN: 151926 Hom.: 25315 Cov.: 31 AF XY: 0.572 AC XY: 42513 AN XY: 74260

Gnomad4 AFR AF: 0.434

Gnomad4 AMR AF: 0.557

Gnomad4 ASJ AF: 0.586

Gnomad4 EAS AF: 0.485

Gnomad4 SAS AF: 0.647

Gnomad4 FIN AF: 0.675

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.608

Alfa AF: 0.612 Hom.: 9258

Bravo AF: 0.551

Asia WGS AF: 0.578 AC: 2011 AN: 3476

EpiCase AF: 0.654

EpiControl AF: 0.655

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Benign:8

Jan 13, 2015

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

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.1605+6T>C (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7224399T>C] 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 -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 23, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 27, 2023

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.1605+6T>C variant in ACADVL is an intronic variant which occurs in intron 16. The highest population minor allele frequency in gnomAD v2.1.1 is 0.66 in European Finnish 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 ExpertPanel: BA1, BP4. -

not specified Benign:6

Jul 25, 2013

GeneDx

Significance: 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1605+6T>C variant in ACADVL is classified as benign because it has been identified in 59% (167006/280516) of the total chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.0
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0072
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.040		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: rs17671352; hg19: chr17-7127718; COSMIC: COSV50040336; COSMIC: COSV50040336;