ENST00000491753.2:n.-788C>A

Variant names:

• chr17-7220526-G-T
• NM_000018.4:c.201G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000018.4(ACADVL):​c.201G>T​(p.Lys67Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K67K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247
• Publications: 0 publications found

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)

ACMG classification

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=0.13808745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.201G>T	p.Lys67Asn	missense_variant	Exon 3 of 20	ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.201G>T	p.Lys67Asn	missense_variant	Exon 3 of 20	1	NM_000018.4	ENSP00000349297.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.16	.;T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.59	T;T;T;T;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.4	.;L;.;.;.
PhyloP100		0.25
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.87	N;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.16	T;.;.;.;.
Sift4G	Benign	0.22	T;T;T;T;D
Polyphen		0.0	.;B;.;.;.
Vest4		0.17
MutPred		0.31		.;Gain of ubiquitination at K64 (P = 0.0232);Gain of ubiquitination at K64 (P = 0.0232);Gain of ubiquitination at K64 (P = 0.0232);Gain of ubiquitination at K64 (P = 0.0232);
MVP		0.85
MPC		0.23
ClinPred		0.25	T
GERP RS		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.067
gMVP		0.26

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

Other links and lift over

hg19: chr17-7123845; COSMIC: COSV99138508; COSMIC: COSV99138508;