chr17-7223687-C-G

Variant names:

• chr17-7223687-C-G
• rs113994169
• NM_000018.4:c.1226C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_000018.4(ACADVL):​c.1226C>G​(p.Thr409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T409M) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 1.22
• Publications: 7 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr17-7223687-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 21013.
• PP5: Variant 17-7223687-C-G is Pathogenic according to our data. Variant chr17-7223687-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1397628.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19626749). . Strength limited to SUPPORTING due to the PP5.

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.1226C>G	p.Thr409Arg	missense	Exon 12 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.1295C>G	p.Thr432Arg	missense	Exon 13 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.1160C>G	p.Thr387Arg	missense	Exon 11 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.1226C>G	p.Thr409Arg	missense	Exon 12 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.1160C>G	p.Thr387Arg	missense	Exon 11 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.1295C>G	p.Thr432Arg	missense	Exon 13 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251476 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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 Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Uncertain	0.63	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	-0.065	N
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.37
Sift	Benign	0.48	T
Sift4G	Benign	0.48	T
Polyphen		0.77	P
Vest4		0.43
MutPred		0.40		Gain of solvent accessibility (P = 0.0503)
MVP		0.91
MPC		0.41
ClinPred		0.13	T
GERP RS		2.6
PromoterAI		-0.0014	Neutral
Varity_R		0.12
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs113994169; hg19: chr17-7127006;