Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4BP7

This summary comes from the ClinGen Evidence Repository: The c.1533G>A (p.Arg511=) variant is a synonymous (silent) variant that is not predicted by (SpliceAI, MaxEntScn, NNSplice) to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by the 100 vertebrate Basewise Conservation by PhyloP track in the UCSC genome browser (BP4, BP7). This variant is absent from gnomAD v2.1.1; however, this is not considered conflicting evidence with BP4 and BP7. In summary, this variant meets the criteria to be classified as likely benign for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BP4, BP7 (ACADVL VCEP specifications version 1; approved November 8, 2021) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10587278/MONDO:0008723/021

Frequency

Genomes: not found (cov: 32)

Consequence

ACADVL
NM_000018.4 splice_region, synonymous

Scores

Splicing: ADA: 0.004835

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 1.45

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

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

BP7

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
ACADVL	NM_000018.4	MANE Select	c.1533G>A	p.Arg511Arg	splice_region synonymous	Exon 16 of 20	NP_000009.1
ACADVL	NM_001270447.2		c.1602G>A	p.Arg534Arg	splice_region synonymous	Exon 17 of 21	NP_001257376.1
ACADVL	NM_001033859.3		c.1467G>A	p.Arg489Arg	splice_region synonymous	Exon 15 of 19	NP_001029031.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1533G>A	p.Arg511Arg	splice_region synonymous	Exon 16 of 20	ENSP00000349297.5
ACADVL	ENST00000350303.9	TSL:1	c.1467G>A	p.Arg489Arg	splice_region synonymous	Exon 15 of 19	ENSP00000344152.5
ACADVL	ENST00000579546.1	TSL:5	c.271G>A	p.Ala91Thr	missense splice_region	Exon 5 of 9	ENSP00000464254.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Very long chain acyl-CoA dehydrogenase deficiency (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0048

dbscSNV1_RF

Benign

0.20

SpliceAI score (max)

0.010

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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rs886038214

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over