rs750653177

Variant names:

• chr17-7220827-C-A
• rs750653177
• NM_000018.4:c.339C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-7220827-C-A
• chr17-7220827-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2_Supporting PM3 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.339C>A variant in ACADVL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 113 (p.(Phe113Leu)). The variant has been identified in at least one individual identified by newborn screen for very long chain acyl CoA dehydrogenase (VLCAD) deficiency with a distinct pathogenic variant and was confirmed in trans by parental testing (PM3 points = 1.0; PMID:21932095; c.848T>C, p.(Val243Ala) ClinVar Variation ID: 21025) (PM3). This individual had NBS C14:1 levels (1.10 uM) above the threshold of ≥ 1.0 μM as specified by the ClinGen ACADVL VCEP. Determination of residual VLCAD activity was performed in lymphocytes derived from this individual and these cells retained 22% ACADVL activity (PMID:21932095) (PP4_Moderate). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.722 which is less than the threshold of 0.75 recommended by ClinGen ACADVL VCEP. In summary, this variant meets the criteria to be classified as 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: PM3, PP4_Moderate, PM2_Supporting (ClinGen ACADVL VCEP specifications version #1.0; approved 2022-12-13) LINK:https://erepo.genome.network/evrepo/ui/classification/CA397722617/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ACADVL NM_000018.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: -0.789
• 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.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.339C>A	p.Phe113Leu	missense	Exon 5 of 20	NP_000009.1
	ACADVL	NM_001270447.2		c.408C>A	p.Phe136Leu	missense	Exon 6 of 21	NP_001257376.1
	ACADVL	NM_001033859.3		c.273C>A	p.Phe91Leu	missense	Exon 4 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.339C>A	p.Phe113Leu	missense	Exon 5 of 20	ENSP00000349297.5
	ACADVL	ENST00000350303.9	TSL:1	c.273C>A	p.Phe91Leu	missense	Exon 4 of 19	ENSP00000344152.5
	ACADVL	ENST00000543245.6	TSL:2	c.408C>A	p.Phe136Leu	missense	Exon 6 of 21	ENSP00000438689.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461754 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727160

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

American (AMR) AF: 0.00 AC: 0 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: 53296

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	1	-	Very long chain acyl-CoA dehydrogenase deficiency (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.5	L
PhyloP100		-0.79
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.72
Sift	Benign	0.098	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.52		Loss of glycosylation at S110 (P = 0.096)
MVP		0.92
MPC		0.26
ClinPred		0.99	D
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.68
Mutation Taster		=17/83	disease causing (ClinVar)

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: rs750653177; hg19: chr17-7124146;