rs150149784

Variant names:

• chr17-7222242-G-C
• rs150149784
• NM_000018.4:c.818G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-7222242-G-C
• chr17-7222242-G-T

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 3P and 4B. PM3_Supporting BS1 PP3 PP4

This summary comes from the ClinGen Evidence Repository: The NM_000018.4(ACADVL):c.818G>C (p.Gly273Ala) in ACADVL is a missense variant predicted to cause substitution of glycine by alanine at amino acid 273 (p. Gly273Ala). The highest population minor allele frequency in gnomAD v3.1.2 is 0.003621 in African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.0035) for BS1, and therefore meets this criterion (BS1). At least one patient with this variant displayed an increased C14:1 level, which is highly specific for very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PP4_Supporting, PMID:24503138), from whom a pathogenic variant was also identified with unknown phase (PM3 point 0.5, PM3_Supporting, PMID:24503138). At least one individual with this variant was identified by newborn screen, but this information is insufficient for to use toward classification (PMID:32778825). The computational predictor REVEL gives a score of 0.933, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: BS1, PP4_Supporting, PM3_Supporting, PP3) LINK:https://erepo.genome.network/evrepo/ui/classification/CA312255/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ACADVL NM_001270447.2 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:8 B:1
• Conservation: PhyloP100: 8.38
• 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: G2P, Orphanet, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• 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.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.818G>C	p.Gly273Ala	missense	Exon 9 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.887G>C	p.Gly296Ala	missense	Exon 10 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.752G>C	p.Gly251Ala	missense	Exon 8 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.818G>C	p.Gly273Ala	missense	Exon 9 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.752G>C	p.Gly251Ala	missense	Exon 8 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.887G>C	p.Gly296Ala	missense	Exon 10 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000294

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000274 AC: 69 AN: 251436 AF XY: 0.000221

Gnomad AFR exome AF: 0.00363

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 198 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.000117 AC XY: 85 AN XY: 727232

African (AFR) AF: 0.00430 AC: 144 AN: 33480

American (AMR) AF: 0.000313 AC: 14 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: 53400

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

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1112004

Other (OTH) AF: 0.000298 AC: 18 AN: 60392

GnomAD4 genome AF: 0.00114 AC: 173 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00111 AC XY: 83 AN XY: 74448

African (AFR) AF: 0.00361 AC: 150 AN: 41546

American (AMR) AF: 0.00124 AC: 19 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000181 Hom.: 0

Bravo AF: 0.00158

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	5	1	Very long chain acyl-CoA dehydrogenase deficiency (6)
-	2	-	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.10	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	2.0	M
PhyloP100		8.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.86
MVP		0.99
MPC		0.79
ClinPred		0.12	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.73
Mutation Taster		=6/94	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: rs150149784; hg19: chr17-7125561;