rs750441118

Positions:

• chr17-7223637-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP4 PP3 PM2_Supporting PM3_Supporting

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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 0.0570

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADVL	NM_000018.4	c.1183-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000356839.10	NP_000009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADVL	ENST00000356839.10	c.1183-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000018.4	ENSP00000349297	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Very long chain acyl-CoA dehydrogenase deficiency Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Nov 01, 2019	The NM_000018.3:c.1183-7A>G (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7223637A>G] variant in ACADVL gene is interpretated to be Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PP4 -
Uncertain significance, reviewed by expert panel	curation	ClinGen ACADVL Variant Curation Expert Panel, ClinGen	Sep 22, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 02, 2021	This sequence change falls in intron 11 of the ACADVL gene. It does not directly change the encoded amino acid sequence of the ACADVL protein. This variant is present in population databases (rs750441118, ExAC 0.001%). This variant has been observed in individual(s) with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 31031081). ClinVar contains an entry for this variant (Variation ID: 567061). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 23, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 25, 2023

Variant summary: ACADVL c.1183-7A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site, and three predict the variant creates a cryptic 3' acceptor site located 6 nucleotides upstream into intron 11. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1183-7A>G has been reported in the literature in at least one compound heterozygous individuals affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Rovelli_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	23
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs750441118; hg19: chr17-7126956;