rs34153370

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The c.68G>A variant in ACADVL is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid 23 (p.Arg23Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01223 in the Latino 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 0.123, 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 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 Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA341524/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 8 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: 0.460

Publications

3 publications found

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:2903): (discs large MAGUK scaffold protein 4) This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DLG4 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual developmental disorder 62
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 link	c.68G>A	p.Arg23Gln	missense_variant	Exon 2 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 link	c.68G>A	p.Arg23Gln	missense_variant	Exon 2 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00200

AC:

335

AN:

167218

AF XY:

0.00135

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.000292

AC:

413

AN:

1413968

Hom.:

Cov.:

AF XY:

0.000223

AC XY:

156

AN XY:

700272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33134

American (AMR)

AF:

0.0105

AC:

401

AN:

38338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25370

East Asian (EAS)

AF:

0.00

AC:

AN:

38590

South Asian (SAS)

AF:

0.00

AC:

AN:

82134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095858

Other (OTH)

AF:

0.000186

AC:

AN:

59070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000387

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.00372

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68008

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000858

ExAC

AF:

0.00110

AC:

123

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency

Benign:6

Oct 27, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2022

ClinGen ACADVL Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.68G>A variant in ACADVL is a missense variant predicted to cause the substitution of arginine by glutamine at amino acid 23 (p.Arg23Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.01223 in the Latino 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 0.123, 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 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 Expert Panel: BA1, BP4 (VCEP specifications v2.0, approved on 09/16/2021). -

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.68G>A (NP_000009.1:p.Arg23Gln) [GRCH38: NC_000017.11:g.7220127G>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 -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Oct 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 02, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 20301763) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

ACADVL-related disorder

Benign:1

Apr 04, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

.;T;.;.;.;T

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.061

LIST_S2

Benign

0.85

T;T;T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

2.0

.;M;.;M;.;.

PhyloP100

0.46

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.62

N;.;.;N;.;.

REVEL

Benign

0.12

Sift

Benign

0.038

D;.;.;T;.;.

Sift4G

Benign

0.38

T;T;T;T;T;T

Polyphen

0.0060, 0.011

.;B;.;B;.;.

Vest4

0.25

MVP

0.87

MPC

0.23

ClinPred

0.036

GERP RS

2.7

PromoterAI

-0.019

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Varity_R

0.076

gMVP

0.15

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over