Genetic Variant NM_000018.4:c.398G>T (chr17-7220979-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000018.4(ACADVL):c.398G>T(p.Trp133Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W133R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.24

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000018.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20684955).

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.398G>T	p.Trp133Leu	missense	Exon 6 of 20	NP_000009.1
ACADVL	NM_001270447.2		c.467G>T	p.Trp156Leu	missense	Exon 7 of 21	NP_001257376.1
ACADVL	NM_001033859.3		c.332G>T	p.Trp111Leu	missense	Exon 5 of 19	NP_001029031.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.398G>T	p.Trp133Leu	missense	Exon 6 of 20	ENSP00000349297.5
ACADVL	ENST00000350303.9	TSL:1	c.332G>T	p.Trp111Leu	missense	Exon 5 of 19	ENSP00000344152.5
ACADVL	ENST00000543245.6	TSL:2	c.467G>T	p.Trp156Leu	missense	Exon 7 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Uncertain

0.52

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.44

M_CAP

Benign

0.032

MetaRNN

Benign

0.21

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

-0.61

PhyloP100

4.2

PrimateAI

Benign

0.32

PROVEAN

Benign

2.9

REVEL

Uncertain

0.47

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.37

MutPred

0.79

Gain of disorder (P = 0.0332)

MVP

0.67

MPC

0.34

ClinPred

0.072

GERP RS

1.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.14

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over