NM_000018.4:c.49C>T

Variant names:

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.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

Publications

11 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000018.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADVL	NM_000018.4	MANE Select	c.49C>T	p.Leu17Phe	missense	Exon 1 of 20	NP_000009.1	P49748-1
ACADVL	NM_001033859.3		c.49C>T	p.Leu17Phe	missense	Exon 1 of 19	NP_001029031.1	P49748-2
DLG4	NM_001321074.1		c.-1184G>A		5_prime_UTR	Exon 1 of 22	NP_001308003.1	B9EGL1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.49C>T	p.Leu17Phe	missense	Exon 1 of 20	ENSP00000349297.5	P49748-1
ACADVL	ENST00000350303.9	TSL:1	c.49C>T	p.Leu17Phe	missense	Exon 1 of 19	ENSP00000344152.5	P49748-2
ACADVL	ENST00000945302.1		c.49C>T	p.Leu17Phe	missense	Exon 1 of 20	ENSP00000615361.1

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

GnomAD2 exomes

AF:

0.00512

AC:

1174

AN:

229122

AF XY:

0.00387

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 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

African (AFR)

AF:

0.0676

AC:

2259

AN:

33440

American (AMR)

AF:

0.00441

AC:

196

AN:

44460

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.000105

AC:

AN:

85780

European-Finnish (FIN)

AF:

0.0000429

AC:

AN:

46588

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000111

AC:

123

AN:

1110898

Other (OTH)

AF:

0.00372

AC:

224

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

180

360

539

719

899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0191

AC:

2906

AN:

152288

Hom.:

100

Cov.:

AF XY:

0.0180

AC XY:

1340

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0657

AC:

2729

AN:

41552

American (AMR)

AF:

0.00778

AC:

119

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68022

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

141

283

424

566

707

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00287

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

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (6)

not provided (5)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.15

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0080

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.6

PhyloP100

-0.92

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.42

REVEL

Benign

0.24

Sift

Benign

0.30

Sift4G

Benign

0.069

Polyphen

0.0

Vest4

0.28

MVP

0.74

ClinPred

0.016

GERP RS

-4.7

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.050

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over