Variant rs17671352 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

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_donor_region, intron

Scores

Splicing: ADA: 0.007159

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: -0.253

Variant links:

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]

ACADVL links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.1605+6T>C		splice_donor_region_variant, intron_variant		ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.1605+6T>C		splice_donor_region_variant, intron_variant		1	NM_000018.4	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.569

AC:

86437

AN:

151808

Hom.:

25290

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.620

AC XY:

450287

AN XY:

726846

show subpopulations

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.:

AF XY:

0.572

AC XY:

42513

AN XY:

74260

show subpopulations

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

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Benign:8

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Jun 27, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	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 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 23, 2022	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 17, 2020	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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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

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