rs2230178

Positions:

chr17-7220187-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP4BP2

This summary comes from the ClinGen Evidence Repository: The c.128G>A variant in ACADVL is well characterized as a benign polymorphism, being present in several VLCAD cases with alternate pathogenic variants (BP2; PMIDs: 11914034, 15210884, more in literature). The highest population minor allele frequency in gnomAD v2.1.1 is 0.17 in the East Asian 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 0.259, 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; BP2; BP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA341517/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.029 ( 144 hom., cov: 33)

Exomes 𝑓: 0.014 ( 868 hom. )

Consequence

ACADVL
NM_001270448.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: 0.732

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:

ACADVL (HGNC:):

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP2

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

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.128G>A	p.Gly43Asp	missense_variant	2/20	ENST00000356839.10	NP_000009.1	P49748-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 linkuse as main transcript	c.128G>A	p.Gly43Asp	missense_variant	2/20	1	NM_000018.4	ENSP00000349297.5		P49748-1

Frequencies

GnomAD3 genomes

AF:

0.0292

AC:

4450

AN:

152190

Hom.:

143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0418

Gnomad ASJ

AF:

0.0389

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.0302

Gnomad FIN

AF:

0.0260

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00609

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0361

AC:

4696

AN:

129906

Hom.:

226

AF XY:

0.0334

AC XY:

2371

AN XY:

71024

show subpopulations

Gnomad AFR exome

AF:

0.0459

Gnomad AMR exome

AF:

0.0561

Gnomad ASJ exome

AF:

0.0361

Gnomad EAS exome

AF:

0.171

Gnomad SAS exome

AF:

0.0188

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.00541

Gnomad OTH exome

AF:

0.0272

GnomAD4 exome

AF:

0.0143

AC:

19801

AN:

1381352

Hom.:

868

Cov.:

AF XY:

0.0143

AC XY:

9762

AN XY:

681450

show subpopulations

Gnomad4 AFR exome

AF:

0.0464

Gnomad4 AMR exome

AF:

0.0548

Gnomad4 ASJ exome

AF:

0.0380

Gnomad4 EAS exome

AF:

0.189

Gnomad4 SAS exome

AF:

0.0202

Gnomad4 FIN exome

AF:

0.0208

Gnomad4 NFE exome

AF:

0.00443

Gnomad4 OTH exome

AF:

0.0252

GnomAD4 genome

AF:

0.0293

AC:

4459

AN:

152308

Hom.:

144

Cov.:

AF XY:

0.0316

AC XY:

2350

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0458

Gnomad4 AMR

AF:

0.0421

Gnomad4 ASJ

AF:

0.0389

Gnomad4 EAS

AF:

0.168

Gnomad4 SAS

AF:

0.0300

Gnomad4 FIN

AF:

0.0260

Gnomad4 NFE

AF:

0.00610

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0154

Hom.:

Bravo

AF:

0.0336

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.0266

AC:

ESP6500EA

AF:

0.00452

AC:

ExAC

AF:

0.0189

AC:

1238

Asia WGS

AF:

0.0950

AC:

330

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Benign:7

Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 22, 2022	The c.128G>A variant in ACADVL is well characterized as a benign polymorphism, being present in several VLCAD cases with alternate pathogenic variants (BP2; PMIDs: 11914034, 15210884, more in literature). The highest population minor allele frequency in gnomAD v2.1.1 is 0.17 in the East Asian 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 0.259, 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; BP2; 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	- -
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.128G>A (NP_000009.1:p.Gly43Asp) [GRCH38: NC_000017.11:g.7220187G>A] 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

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)	Aug 28, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.17

.;T;.;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.81

T;T;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.1

.;M;.;M;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.52

N;.;.;N;.;.

REVEL

Benign

0.26

Sift

Benign

0.35

T;.;.;T;.;.

Sift4G

Benign

0.10

T;T;T;T;T;T

Polyphen

0.041, 0.020

.;B;.;B;.;.

Vest4

0.094

MPC

0.39

ClinPred

0.0030

GERP RS

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.043

gMVP

0.31

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