NM_000018.4:c.1733T>C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000018.4(ACADVL):c.1733T>C(p.Met578Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,522,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M578V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 6.50

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 Gene-Disease associations (from GenCC):

very long chain acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACADVL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000018.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

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
ACADVL	NM_000018.4	MANE Select	c.1733T>C	p.Met578Thr	missense	Exon 18 of 20	NP_000009.1
ACADVL	NM_001270447.2		c.1802T>C	p.Met601Thr	missense	Exon 19 of 21	NP_001257376.1
ACADVL	NM_001033859.3		c.1667T>C	p.Met556Thr	missense	Exon 17 of 19	NP_001029031.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1733T>C	p.Met578Thr	missense	Exon 18 of 20	ENSP00000349297.5
ACADVL	ENST00000350303.9	TSL:1	c.1667T>C	p.Met556Thr	missense	Exon 17 of 19	ENSP00000344152.5
ACADVL	ENST00000543245.6	TSL:2	c.1802T>C	p.Met601Thr	missense	Exon 19 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes

AF:

0.0000858

AC:

AN:

139926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000320

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD2 exomes

AF:

0.00000938

AC:

AN:

213112

AF XY:

0.00000865

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000578

AC:

AN:

1382976

Hom.:

Cov.:

AF XY:

0.00000729

AC XY:

AN XY:

685908

show subpopulations

African (AFR)

AF:

0.000128

AC:

AN:

31152

American (AMR)

AF:

0.00

AC:

AN:

39340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23446

East Asian (EAS)

AF:

0.00

AC:

AN:

34124

South Asian (SAS)

AF:

0.00

AC:

AN:

83386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5258

European-Non Finnish (NFE)

AF:

0.00000376

AC:

AN:

1063328

Other (OTH)

AF:

0.00

AC:

AN:

55522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000857

AC:

AN:

139994

Hom.:

Cov.:

AF XY:

0.0000445

AC XY:

AN XY:

67394

show subpopulations

African (AFR)

AF:

0.000320

AC:

AN:

37526

American (AMR)

AF:

0.00

AC:

AN:

12978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3414

East Asian (EAS)

AF:

0.00

AC:

AN:

4418

South Asian (SAS)

AF:

0.00

AC:

AN:

4212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66072

Other (OTH)

AF:

0.00

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000658

Hom.:

Bravo

AF:

0.0000604

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000414

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (4)

not provided (3)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Benign

0.90

DEOGEN2

Uncertain

0.70

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

0.65

MutationAssessor

Pathogenic

3.1

PhyloP100

6.5

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.80

MVP

0.98

MPC

0.63

ClinPred

0.86

GERP RS

5.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.82

gMVP

0.93

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over