NM_000018.4:c.439C>T

Variant names:

• chr17-7221020-C-T
• rs1032857886
• NM_000018.4:c.439C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PM3_Supporting PP3 PP4

This summary comes from the ClinGen Evidence Repository: The c.439C>T (p.Pro147Ser) variant in ACADVL is a missense in exon 6. This variant has been reported once in the literature in a proband with very-long chain acyl-CoA dehydrogenase deficiency, and elevated C14:1 in NBS (PP4, PMID27209629). This variant is absent from population databases gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.88, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). However, there is insufficient experimental or case data identified in the literature for this variant and is therefore classified as a VUS. (ACADVL-specific ACMG/AMP criteria applied: PP4; PM2_supporting; PP3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA287435425/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 5.22
• Publications: 3 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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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.439C>T	p.Pro147Ser	missense	Exon 6 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.508C>T	p.Pro170Ser	missense	Exon 7 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.373C>T	p.Pro125Ser	missense	Exon 5 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.439C>T	p.Pro147Ser	missense	Exon 6 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.373C>T	p.Pro125Ser	missense	Exon 5 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.508C>T	p.Pro170Ser	missense	Exon 7 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461738 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	-	Very long chain acyl-CoA dehydrogenase deficiency (4)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.2
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.81		Gain of sheet (P = 0.0827)
MVP		0.98
MPC		0.77
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.90
Mutation Taster		=0/100	disease causing

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

dbSNP: rs1032857886; hg19: chr17-7124339;