dbSNP rs113994171: ACADVL:c.1679-6G>A (chr17-7224636-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2_SupportingPM3_StrongPS3_SupportingPP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1679-6G>A variant in ACADVL is an intronic variant which creates a novel acceptor site in intron 17, experimentally shown to cause insertion of four nucleotides and causes a frameshift (PS3_Supporting; PMID:9709714). This variant has been reported in several individuals affected with very long chain acyl CoA dehydrogenase (VLCAD) deficiency confirmed in trans to at least one pathogenic variant, presumed in trans to distinct ACADVL variants, and in the homozygous state in at least two individuals (PM3_Strong; PMIDs:23480858, 9709714, 8845838). Fibroblasts derived from one of these individuals showed no detectable VLCAD activity, which is highly specific for VLCAD deficiency (PP4_Moderate; PMID:234808). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0002264 in the Latino/Admixed American population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PS3_Supporting, PM3_Strong, PM2_Supporting, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 8, 2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA312281/MONDO:0008723/021

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 splice_region, intron

Scores

Splicing: ADA: 0.8467

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 0.212

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: Likely_pathogenic. The variant received 8 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.

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	Effect	Exon Rank	Protein	UniProt
ACADVL	NM_000018.4	MANE Select	c.1679-6G>A	splice_region intron	N/A	NP_000009.1	P49748-1
ACADVL	NM_001270447.2		c.1748-6G>A	splice_region intron	N/A	NP_001257376.1	P49748-3
ACADVL	NM_001033859.3		c.1613-6G>A	splice_region intron	N/A	NP_001029031.1	P49748-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1679-6G>A	splice_region intron	N/A	ENSP00000349297.5	P49748-1
ACADVL	ENST00000350303.9	TSL:1	c.1613-6G>A	splice_region intron	N/A	ENSP00000344152.5	P49748-2
ACADVL	ENST00000543245.6	TSL:2	c.1748-6G>A	splice_region intron	N/A	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

15944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000828

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:

0.0000217

AC:

AN:

92036

AF XY:

0.0000396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000226

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:

0.0000746

AC:

AN:

388802

Hom.:

Cov.:

AF XY:

0.0000828

AC XY:

AN XY:

193228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9418

American (AMR)

AF:

0.000225

AC:

AN:

13342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7506

East Asian (EAS)

AF:

0.00

AC:

AN:

5918

South Asian (SAS)

AF:

0.00

AC:

AN:

29000

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1424

European-Non Finnish (NFE)

AF:

0.0000892

AC:

AN:

291598

Other (OTH)

AF:

0.00

AC:

AN:

14240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000626

AC:

AN:

15978

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

8226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

3614

American (AMR)

AF:

0.000825

AC:

AN:

1212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

460

East Asian (EAS)

AF:

0.00

AC:

AN:

582

South Asian (SAS)

AF:

0.00

AC:

AN:

604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

8556

Other (OTH)

AF:

0.00

AC:

AN:

258

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

Alfa

AF:

0.0000396

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (9)

ACADVL-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Uncertain

(source)

DANN

Benign

0.82

PhyloP100

0.21

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.85

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.99

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over