rs200788251

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2_SupportingPM3PS3_SupportingPP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: The c.865G>A (p.Gly289Arg) variant in ACADVL has been reported in the literature in patients with VLCADD and increased C14:1 acylcarnitine (PP4_moderate; PMID:14517516, 23480858, 31031081, 32778825, 27209629). The variant has also been detected in compound heterozygote with truncating/pathogenic variants (PM3; PMID:14517516, 23480858, 31031081). This variant is absent from gnomAD population database v2.1.1(PM2_Supporting). This variant causes significantly reduced enzyme activity (15% of WT) determined from a bacterial cell expression system and results in unstable protein product (PMID:23480858, PS3_supporting). The computational predictor REVEL gives a score of 0.824, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). The ACADVL Variant Curation Expert Panel VCEP classified the variant as likely pathogenic based on (PS3_supporting, PM3, PM2_supporting, PP3, PP4_moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8337873/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

10

6

2

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 8.34

Publications

14 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

Specifications for ACADVL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.865G>A	p.Gly289Arg	missense	Exon 9 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.934G>A	p.Gly312Arg	missense	Exon 10 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.799G>A	p.Gly267Arg	missense	Exon 8 of 19	NP_001029031.1	P49748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.865G>A	p.Gly289Arg	missense	Exon 9 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.799G>A	p.Gly267Arg	missense	Exon 8 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.934G>A	p.Gly312Arg	missense	Exon 10 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

20

AN:

152136

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000107

AC:

27

AN:

251232

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000220

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000201

AC:

294

AN:

1461744

Hom.:

0

Cov.:

32

AF XY:

0.000191

AC XY:

139

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.000119

AC:

4

AN:

33480

American (AMR)

AF:

0.0000224

AC:

1

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

11

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86254

European-Finnish (FIN)

AF:

0.0000188

AC:

1

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.000228

AC:

254

AN:

1111978

Other (OTH)

AF:

0.000381

AC:

23

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0

21

43

64

86

107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

10

20

30

40

50

<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:

0.000131

AC:

20

AN:

152254

Hom.:

0

Cov.:

32

AF XY:

0.0000806

AC XY:

6

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0000241

AC:

1

AN:

41520

American (AMR)

AF:

0.0000654

AC:

1

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

1

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

16

AN:

68020

Other (OTH)

AF:

0.000473

AC:

1

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

0

1

3

4

6

7

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

0

2

4

6

8

10

<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:

0.000304

Hom.:

0

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.000349

AC:

3

ExAC

AF:

0.0000906

AC:

11

EpiCase

AF:

0.000273

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

10

-

-

Very long chain acyl-CoA dehydrogenase deficiency (10)

1

-

-

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Pathogenic

0.21

D

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Pathogenic

0.74

D

MetaRNN

Pathogenic

0.88

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Benign

1.5

L

PhyloP100

8.3

PrimateAI

Uncertain

0.64

T

PROVEAN

Pathogenic

-7.0

D

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

D

Sift4G

Uncertain

0.011

D

Polyphen

1.0

D

Vest4

0.90

MutPred

0.81

Gain of solvent accessibility (P = 0.0306)

MVP

0.99

MPC

0.80

ClinPred

0.73

D

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.78

Mutation Taster

=0/100

disease causing (ClinVar)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs200788251; hg19: chr17-7125608; COSMIC: COSV107204129; COSMIC: COSV107204129; API

⚠️ JavaScript appears to be disabled in your browser.
To fully enjoy Genebe.net, please enable JavaScript.
All interactive features require JS to work properly.