rs747351687
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000018.4(ACADVL):c.138+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.00000196 in 1,532,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ACADVL
NM_000018.4 splice_donor
NM_000018.4 splice_donor
Scores
3
3
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.29
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 17-7220198-G-A is Pathogenic according to our data. Variant chr17-7220198-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550796.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADVL | NM_000018.4 | c.138+1G>A | splice_donor_variant | ENST00000356839.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADVL | ENST00000356839.10 | c.138+1G>A | splice_donor_variant | 1 | NM_000018.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
1
AN:
152230
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00000775 AC: 1AN: 128992Hom.: 0 AF XY: 0.0000142 AC XY: 1AN XY: 70506
GnomAD3 exomes
AF:
AC:
1
AN:
128992
Hom.:
AF XY:
AC XY:
1
AN XY:
70506
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000145 AC: 2AN: 1379888Hom.: 0 Cov.: 35 AF XY: 0.00000294 AC XY: 2AN XY: 680636
GnomAD4 exome
AF:
AC:
2
AN:
1379888
Hom.:
Cov.:
35
AF XY:
AC XY:
2
AN XY:
680636
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74380
GnomAD4 genome
?
AF:
AC:
1
AN:
152230
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
74380
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
?
AF:
AC:
1
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Very long chain acyl-CoA dehydrogenase deficiency Pathogenic:5
Likely pathogenic, reviewed by expert panel | curation | ClinGen ACADVL Variant Curation Expert Panel, ClinGen | Apr 06, 2022 | The c.138+1G>A (p.?) (NM_000018.4) variant in ACADVL occurs within the canonical splice acceptor site (+1) of intron 2. It is predicted to cause skipping of biologically-relevant-exon 2/20, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMIDs: 9973285, 11590124). The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (1/22352 alleles) in SAS population, which is lower than the ClinGen ACADVL VCEP threshold (<0.1%) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient with this variant in a heterozygous state was positive at NBS or presumed NBS positive; the second allele was not clearly stated (PMID: 26385305). To our knowledge, functional assays have not been reported for this variant. To our knowledge, this variant has not been reported in the literature for segregation in family members affected with VLCADD. In summary, this variant has been classified as likely pathogenic for autosomal recessive very long chain acyl-CoA dehydrogenase deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Curation Expert Panel: PVS1, PM2_Supporting (ACADVL VCEP specifications v2.0; Approved on 11/10/2021). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2023 | Disruption of this splice site has been observed in individual(s) with very long-chain acyl-CoA dehydrogenase deficiency (PMID: 26385305). This sequence change affects a donor splice site in intron 2 of the ACADVL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADVL are known to be pathogenic (PMID: 9973285, 11590124). This variant is present in population databases (rs747351687, gnomAD 0.004%). ClinVar contains an entry for this variant (Variation ID: 550796). 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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Pathogenic, 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.138+1G>A (NP_000009.1:p.?) [GRCH38: NC_000017.11:g.7220198G>A] variant in ACADVL gene is interpretated to be Pathogenic based on ACMG guidelines (PMID: 25741868). This variant has been reported. This variant meets the following evidence codes reported in the ACMG guidelines: PVS1, PS3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 10, 2021 | Variant summary: ACADVL c.138+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.8e-06 in 128992 control chromosomes (gnomAD). c.138+1G>A has been reported in the literature in atleast one individual affected with Very Long Chain Acyl-CoA Dehydrogenase Deficiency (Miller_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at