17-7220979-G-C

Variant names:

• chr17-7220979-G-C
• rs1555527907
• NM_000018.4:c.398G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_001270447.2(ACADVL):​c.467G>C​(p.Trp156Ser) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W156R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADVL NM_001270447.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.24
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001270447.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270447.2. 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.398G>C	p.Trp133Ser	missense	Exon 6 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.467G>C	p.Trp156Ser	missense	Exon 7 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.332G>C	p.Trp111Ser	missense	Exon 5 of 19	NP_001029031.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.398G>C	p.Trp133Ser	missense	Exon 6 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.332G>C	p.Trp111Ser	missense	Exon 5 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.467G>C	p.Trp156Ser	missense	Exon 7 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.7	L
PhyloP100		4.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.59
Sift	Benign	0.033	D
Sift4G	Uncertain	0.051	T
Polyphen		0.021	B
Vest4		0.46
MutPred		0.79		Gain of disorder (P = 3e-04)
MVP		0.85
MPC		0.31
ClinPred		0.60	D
GERP RS		1.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.21
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1555527907; hg19: chr17-7124298;