rs2230179

Positions:

chr17-7220033-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.49C>T variant in ACADVL has been reported as part of premature screening panels, however no probands have shown increased VLCAD activity or newborn screening (PMID:23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06989 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 computational predictor REVEL gives a score of 0.236, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA341522/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.019 ( 100 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 78 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:13

Conservation

PhyloP100: -0.916

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:

DLG4 (HGNC:):

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4 linkuse as main transcript	c.49C>T	p.Leu17Phe	missense_variant	1/20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.49C>T	p.Leu17Phe	missense_variant	1/20	1	NM_000018.4	ENSP00000349297	P1	P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2900

AN:

152170

Hom.:

100

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0657

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0186

GnomAD3 exomes

AF:

0.00512

AC:

1174

AN:

229122

Hom.:

AF XY:

0.00387

AC XY:

488

AN XY:

125954

show subpopulations

Gnomad AFR exome

AF:

0.0699

Gnomad AMR exome

AF:

0.00381

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000100

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000215

Gnomad OTH exome

AF:

0.00335

GnomAD4 exome

AF:

0.00195

AC:

2827

AN:

1452620

Hom.:

Cov.:

AF XY:

0.00170

AC XY:

1226

AN XY:

722688

show subpopulations

Gnomad4 AFR exome

AF:

0.0676

Gnomad4 AMR exome

AF:

0.00441

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.0000429

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.00372

GnomAD4 genome

AF:

0.0191

AC:

2906

AN:

152288

Hom.:

100

Cov.:

AF XY:

0.0180

AC XY:

1340

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0657

Gnomad4 AMR

AF:

0.00778

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0184

Alfa

AF:

0.00244

Hom.:

Bravo

AF:

0.0216

ESP6500AA

AF:

0.0641

AC:

280

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.00608

AC:

732

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Benign:6

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.49C>T (NP_000009.1:p.Leu17Phe) [GRCH38: NC_000017.11:g.7220033C>T] 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	Fulgent Genetics, Fulgent Genetics	Dec 15, 2021	- -
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	Sep 22, 2022	The c.49C>T variant in ACADVL has been reported as part of premature screening panels, however no probands have shown increased VLCAD activity or newborn screening (PMID: 23480858). The highest population minor allele frequency in gnomAD v2.1.1 is 0.06989 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 computational predictor REVEL gives a score of 0.236, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets criteria to be classified as benign for very long chain acyl-CoA dehydrogenase deficiency in an autosomal recessive manner. ACADVL-specific ACMG/AMP criteria applied: BA1; BP4 -
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	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2016	Variant summary: c.49C>T affects a non-conserved nucleotide, resulting in amino acid change from Leu to Phe. 4/4 in-silico tools predict this variant to be benign .The variant was observed in the large and broad control population from ExAC with an allele frequency of 0.0071727% (648/90342 chromosomes) which includes 20 homozygous occurrences. The variant is particularly more common in African population with an allele frequency of 8.8% (597/6748 chromosomes) including 20 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.288%) in this gene, suggesting this variant is benign polymorphism found mainly in African population. One reputable database and a clinical lab classify the variant as benign. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.15

T;.;.;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.64

T;T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.6

L;.;L;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.42

.;.;N;.;.

REVEL

Benign

0.24

Sift

Benign

0.30

.;.;T;.;.

Sift4G

Benign

0.069

T;T;T;D;T

Polyphen

0.0

B;.;B;.;.

Vest4

0.28

MVP

0.74

ClinPred

0.016

GERP RS

-4.7

Varity_R

0.050

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.87

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.87

Position offset: -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