dbSNP rs1443151475: ACADVL:p.Pro35LeufsTer26 (chr17-7220160-GC-G) – ACMG Classification: Pathogenic (13 pts)

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2_SupportingPM3PVS1PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.104del (p.(Pro35Leufs*26)) (NM_000018.4) variant in ACADVL is a frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 2/20 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). This variant has been detected in at least 4 individuals with VLCADD. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant and was not confirmed in trans (PM3 0.5 pt, PMID:25834949). 3 individuals were homozygous for the variant (PM3 1.0 point max., PMIDs: 25834949, 32276429) (PM3). The highest population minor allele frequency in gnomAD v2.1.1 is 0.007886%(2/25360 alleles) in AMR population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM3, PP4_Moderate, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 10/11/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA624861220/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: -0.0620

Publications

6 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: Pathogenic. The variant received 13 ACMG points.

PVS1

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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACADVL	NM_000018.4	MANE Select	c.104delC	p.Pro35LeufsTer26	frameshift	Exon 2 of 20	NP_000009.1	P49748-1
ACADVL	NM_001270447.2		c.173delC	p.Pro58LeufsTer26	frameshift	Exon 3 of 21	NP_001257376.1	P49748-3
ACADVL	NM_001033859.3		c.104delC	p.Pro35LeufsTer60	frameshift	Exon 2 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.104delC	p.Pro35LeufsTer26	frameshift	Exon 2 of 20	ENSP00000349297.5	P49748-1
ACADVL	ENST00000350303.9	TSL:1	c.104delC	p.Pro35LeufsTer60	frameshift	Exon 2 of 19	ENSP00000344152.5	P49748-2
ACADVL	ENST00000543245.6	TSL:2	c.173delC	p.Pro58LeufsTer26	frameshift	Exon 3 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000219

AC:

AN:

137290

AF XY:

0.0000267

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000190

Gnomad OTH exome

AF:

0.000244

GnomAD4 exome

AF:

0.00000360

AC:

AN:

1388036

Hom.:

Cov.:

AF XY:

0.00000292

AC XY:

AN XY:

685150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32326

American (AMR)

AF:

0.0000280

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25076

East Asian (EAS)

AF:

0.00

AC:

AN:

36750

South Asian (SAS)

AF:

0.00

AC:

AN:

79834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34264

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4752

European-Non Finnish (NFE)

AF:

0.00000370

AC:

AN:

1081424

Other (OTH)

AF:

0.00

AC:

AN:

57924

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

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:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.062

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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