rs750441118

Variant names:

• chr17-7223637-A-G
• rs750441118
• NM_000018.4:c.1183-7A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2_Supporting PM3_Supporting PP4 PP3

This summary comes from the ClinGen Evidence Repository: The c.1183-7A>G variant in ACADVL occurs within splice acceptor site of intron 11. The results from two in silico splicing predictors (MaxEntScn and Human Splicing Finder) indicate that this variant may affect splicing by disrupting the acceptor splice site of intron 11 of 20 in ACADVL (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). At least one patient with this variant displayed C14:1-carnitine level at 15.5 micromolar, which is highly specific for VLCAD deficiency (PP4_Supporting, PMID:31031081). Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting, and PP4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8338033/MONDO:0008723/021

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ACADVL NM_000018.4 splice_region, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 0.0570
• Publications: 1 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

Specifications for ACADVL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 4 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.
• PP3: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADVL	NM_000018.4	MANE Select	c.1183-7A>G		splice_region intron	N/A	NP_000009.1	P49748-1
	ACADVL	NM_001270447.2		c.1252-7A>G		splice_region intron	N/A	NP_001257376.1	P49748-3
	ACADVL	NM_001033859.3		c.1117-7A>G		splice_region intron	N/A	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.1183-7A>G		splice_region intron	N/A	ENSP00000349297.5	P49748-1
	ACADVL	ENST00000350303.9	TSL:1	c.1117-7A>G		splice_region intron	N/A	ENSP00000344152.5	P49748-2
	ACADVL	ENST00000543245.6	TSL:2	c.1252-7A>G		splice_region intron	N/A	ENSP00000438689.2	P49748-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

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: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111984

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	-	Very long chain acyl-CoA dehydrogenase deficiency (4)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	23
DANN	Benign	0.72
PhyloP100		0.057
PromoterAI		0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.85		Position offset: 1
DS_AL_spliceai		0.85		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs750441118; hg19: chr17-7126956;