NM_000018.4:c.739A>T

Variant names:

• chr17-7222068-A-T
• rs387906253
• NM_000018.4:c.739A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000018.4(ACADVL):​c.739A>T​(p.Lys247*) variant causes a stop gained change involving the alteration of a conserved nucleotide. 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. K247K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay. The gene ACADVL is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADVL NM_000018.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.17
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for ACADVL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-7222068-A-T is Pathogenic according to our data. Variant chr17-7222068-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2857471.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.739A>T	p.Lys247*	stop_gained	Exon 8 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.808A>T	p.Lys270*	stop_gained	Exon 9 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.673A>T	p.Lys225*	stop_gained	Exon 7 of 19	NP_001029031.1	P49748-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.739A>T	p.Lys247*	stop_gained	Exon 8 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.673A>T	p.Lys225*	stop_gained	Exon 7 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.808A>T	p.Lys270*	stop_gained	Exon 9 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Very long chain acyl-CoA dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.2
Vest4		0.88
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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

dbSNP: rs387906253; hg19: chr17-7125387;