rs146379816

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP5BP4

The NM_000018.4(ACADVL):c.1591C>T(p.Arg531Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000805 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R531Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:8

Conservation

PhyloP100: 3.29

Publications

5 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: ClinGen, G2P, Orphanet, 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 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_000018.4

PP5

Variant 17-7224379-C-T is Pathogenic according to our data. Variant chr17-7224379-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166647.

BP4

Computational evidence support a benign effect (MetaRNN=0.29185665). . Strength limited to SUPPORTING due to the PP5.

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.1591C>T	p.Arg531Trp	missense	Exon 16 of 20	NP_000009.1	P49748-1
ACADVL	NM_001270447.2		c.1660C>T	p.Arg554Trp	missense	Exon 17 of 21	NP_001257376.1	P49748-3
ACADVL	NM_001033859.3		c.1525C>T	p.Arg509Trp	missense	Exon 15 of 19	NP_001029031.1	P49748-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1591C>T	p.Arg531Trp	missense	Exon 16 of 20	ENSP00000349297.5	P49748-1
ACADVL	ENST00000350303.9	TSL:1	c.1525C>T	p.Arg509Trp	missense	Exon 15 of 19	ENSP00000344152.5	P49748-2
ACADVL	ENST00000543245.6	TSL:2	c.1660C>T	p.Arg554Trp	missense	Exon 17 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000444

AC:

111

AN:

250116

AF XY:

0.000450

show subpopulations

Gnomad AFR exome

AF:

0.000186

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000934

Gnomad NFE exome

AF:

0.000806

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000852

AC:

1245

AN:

1461564

Hom.:

Cov.:

AF XY:

0.000842

AC XY:

612

AN XY:

727088

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33478

American (AMR)

AF:

0.000291

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53280

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00106

AC:

1182

AN:

1111906

Other (OTH)

AF:

0.000563

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000355

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41534

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000559

AC:

AN:

67992

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000530

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (9)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Uncertain

0.65

Eigen

Benign

0.17

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.29

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.8

PhyloP100

3.3

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.1

REVEL

Uncertain

0.52

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.55

MVP

0.95

MPC

0.64

ClinPred

0.11

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.60

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Computational scores

Splicing

Publications

Other links and lift over