chr17-7220127-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000018.4(ACADVL):c.68G>T(p.Arg23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ACADVL
NM_000018.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.460

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 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

DLG4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21052033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4 link	c.68G>T	p.Arg23Leu	missense_variant	Exon 2 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10 link	c.68G>T	p.Arg23Leu	missense_variant	Exon 2 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1413968

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33134

American (AMR)

AF:

0.00

AC:

AN:

38338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25370

East Asian (EAS)

AF:

0.00

AC:

AN:

38590

South Asian (SAS)

AF:

0.00

AC:

AN:

82134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5352

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095858

Other (OTH)

AF:

0.00

AC:

AN:

59070

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

GnomAD4 genome

Cov.:

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

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 23 of the ACADVL protein (p.Arg23Leu). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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

0.099

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

.;T;.;.;.;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.81

T;T;T;T;T;T

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.21

T;T;T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Uncertain

2.3

.;M;.;M;.;.

PhyloP100

0.46

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.4

N;.;.;N;.;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.0040

D;.;.;D;.;.

Sift4G

Benign

0.26

T;T;T;T;D;D

Polyphen

0.099, 0.16

.;B;.;B;.;.

Vest4

0.47

MutPred

0.35

.;Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);

MVP

0.91

MPC

0.28

ClinPred

0.47

GERP RS

2.7

PromoterAI

-0.027

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Varity_R

0.21

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over