rs2230178

Positions:

• chr17-7220187-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1 BP4 BP2

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_000018.4 missense
• Clinical Significance: Benign reviewed by expert panel B:10
• Conservation: PhyloP100: 0.732

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 -10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADVL	NM_000018.4	c.128G>A	p.Gly43Asp	missense_variant	2/20	ENST00000356839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADVL	ENST00000356839.10	c.128G>A	p.Gly43Asp	missense_variant	2/20	1	NM_000018.4	P1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4450 AN: 152190 Hom.: 143 Cov.: 33

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

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.: 35 AF XY: 0.0143 AC XY: 9762 AN XY: 681450

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.: 33 AF XY: 0.0316 AC XY: 2350 AN XY: 74478

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.: 8

Bravo AF: 0.0336

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.0266 AC: 74

ESP6500EA AF: 0.00452 AC: 28

ExAC AF: 0.0189 AC: 1238

Asia WGS AF: 0.0950 AC: 330 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: reviewed by expert panel

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, 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.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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
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	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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.17	.;T;.;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
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	T
MutationAssessor	Uncertain	2.1	.;M;.;M;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.44	T
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	T
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

Other links and lift over

dbSNP: rs2230178; hg19: chr17-7123506; COSMIC: COSV57238038; COSMIC: COSV57238038;