17-7220979-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000018.4(ACADVL):​c.398G>C​(p.Trp133Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ACADVL
NM_000018.4 missense

Scores

4
5
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.24
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADVLNM_000018.4 linkc.398G>C p.Trp133Ser missense_variant Exon 6 of 20 ENST00000356839.10 NP_000009.1 P49748-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADVLENST00000356839.10 linkc.398G>C p.Trp133Ser missense_variant Exon 6 of 20 1 NM_000018.4 ENSP00000349297.5 P49748-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:1
Apr 21, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 133 of the ACADVL protein (p.Trp133Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACADVL-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADVL protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Benign
22
DANN
Benign
0.92
DEOGEN2
Uncertain
0.68
.;D;.;.;.;T
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.59
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.82
T;T;T;T;T;T
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Benign
1.7
.;L;.;.;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.47
N;.;.;N;.;.
REVEL
Uncertain
0.59
Sift
Benign
0.033
D;.;.;D;.;.
Sift4G
Uncertain
0.051
T;D;T;D;D;T
Polyphen
0.021, 0.0020
.;B;.;B;.;.
Vest4
0.46
MutPred
0.79
.;Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);.;.;.;
MVP
0.85
MPC
0.31
ClinPred
0.60
D
GERP RS
1.8
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.21
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7124298; API