rs886043236

Variant names:

• chr17-7223871-T-C
• rs886043236
• NM_000018.4:c.1328T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-7223871-T-C
• chr17-7223871-T-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000018.4(ACADVL):​c.1328T>C​(p.Met443Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M443R) 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: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.15
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 chr17-7223871-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 285852.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 17-7223871-T-C is Pathogenic according to our data. Variant chr17-7223871-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1437726.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.1328T>C	p.Met443Thr	missense	Exon 13 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1397T>C	p.Met466Thr	missense	Exon 14 of 21	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1262T>C	p.Met421Thr	missense	Exon 12 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.1328T>C	p.Met443Thr	missense	Exon 13 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1262T>C	p.Met421Thr	missense	Exon 12 of 19	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1397T>C	p.Met466Thr	missense	Exon 14 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251352 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 AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 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: 53320

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Very long chain acyl-CoA dehydrogenase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	24
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.87
Sift	Benign	0.081	T
Sift4G	Benign	0.11	T
Polyphen		0.041	B
Vest4		0.91
MutPred		0.55		Gain of methylation at K444 (P = 0.0249)
MVP		0.95
MPC		0.28
ClinPred		0.39	T
GERP RS		5.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.83
gMVP		0.91
Mutation Taster		=1/99	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: rs886043236; hg19: chr17-7127190;