rs28934585

Variant names:

• chr17-7220519-C-T
• rs28934585
• NM_000018.4:c.194C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BS3_Supporting BA1 BP4

This summary comes from the ClinGen Evidence Repository: The c.194C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by leucine at amino acid 65 (p.Pro65Leu). The highest population minor allele frequency in gnomAD v2.1.1 is 0.1129 in the African/African American population, which is higher than the ClinGen ACADVL Variant Curation Expert Panel threshold (≥0.007) for BA1, and therefore meets this criterion (BA1). Palmitoyl-CoA dehydrogenase activity in VLCAD-null fibroblasts transfected with c.194C>T cDNA showed activity comparable to the cells transfected with wild-type cDNA indicating that this variant does not impact protein function (PMID:10790204, BS3_supporting). The computational predictor REVEL gives a score of 0.276, which is below the threshold of 0.5, evidence that does not predict a damaging effect on ACADVL function (BP4). In summary, this variant meets the criteria to be classified as benign 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: BA1, BS3_supporting, BP4 (VCEP specifications v2.0, approved on 09/16/2021). LINK:https://erepo.genome.network/evrepo/ui/classification/CA285292/MONDO:0008723/021

• Frequency:
  • Genomes: 𝑓 0.032 (248 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (246 hom.)
• Consequence: ACADVL NM_001270448.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: -1.74
• Publications: 21 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: Benign. The variant received -10 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270448.2. 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.194C>T	p.Pro65Leu	missense	Exon 3 of 20	NP_000009.1	P49748-1
	ACADVL	NM_001270448.2		c.-35C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 19	NP_001257377.1	B3KPA6
	ACADVL	NM_001270447.2		c.263C>T	p.Pro88Leu	missense	Exon 4 of 21	NP_001257376.1	P49748-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	ENST00000356839.10	TSL:1 MANE Select	c.194C>T	p.Pro65Leu	missense	Exon 3 of 20	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.139-85C>T		intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.263C>T	p.Pro88Leu	missense	Exon 4 of 21	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4888 AN: 152190 Hom.: 247 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0140

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.00823 AC: 2069 AN: 251436 AF XY: 0.00600

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000325

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00323 AC: 4719 AN: 1461878 Hom.: 246 Cov.: 33 AF XY: 0.00278 AC XY: 2023 AN XY: 727240

African (AFR) AF: 0.110 AC: 3699 AN: 33480

American (AMR) AF: 0.00635 AC: 284 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000522 AC: 45 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000154 AC: 171 AN: 1112010

Other (OTH) AF: 0.00798 AC: 482 AN: 60394

GnomAD4 genome AF: 0.0321 AC: 4895 AN: 152308 Hom.: 248 Cov.: 33 AF XY: 0.0311 AC XY: 2315 AN XY: 74472

African (AFR) AF: 0.111 AC: 4604 AN: 41558

American (AMR) AF: 0.0139 AC: 213 AN: 15312

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68020

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.0136 Hom.: 125

Bravo AF: 0.0362

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0992 AC: 437

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0105 AC: 1273

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Very long chain acyl-CoA dehydrogenase deficiency (6)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	3.9
DANN	Benign	0.71
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.95	L
PhyloP100		-1.7
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.28
Sift	Benign	0.047	D
Sift4G	Benign	0.14	T
Polyphen		0.019	B
Vest4		0.11
MPC		0.20
ClinPred		0.017	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.025
gMVP		0.28
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.010		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: rs28934585; hg19: chr17-7123838; COSMIC: COSV50035622; COSMIC: COSV50035622;