NM_000018.4:c.1198G>T

Variant names:

• chr17-7223659-G-T
• rs149116708
• NM_000018.4:c.1198G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000018.4(ACADVL):​c.1198G>T​(p.Val400Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V400M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.22
• Publications: 6 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 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000018.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-7223659-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 551143.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34808105).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.1198G>T	p.Val400Leu	missense	Exon 12 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.1267G>T	p.Val423Leu	missense	Exon 13 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.1132G>T	p.Val378Leu	missense	Exon 11 of 19	NP_001029031.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.1198G>T	p.Val400Leu	missense	Exon 12 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.1132G>T	p.Val378Leu	missense	Exon 11 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.1267G>T	p.Val423Leu	missense	Exon 13 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251466 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 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: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.033	T
MutationAssessor	Benign	0.62	N
PhyloP100		1.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.40
Sift	Benign	0.52	T
Sift4G	Benign	0.42	T
Polyphen		0.0020	B
Vest4		0.45
MutPred		0.72		Loss of catalytic residue at V400 (P = 9e-04)
MVP		0.78
MPC		0.19
ClinPred		0.17	T
GERP RS		5.0
PromoterAI		-0.060	Neutral
Varity_R		0.33
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149116708; hg19: chr17-7126978;