rs147936696
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001609.4(ACADSB):c.303+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000436 in 1,556,270 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00044 ( 1 hom. )
Consequence
ACADSB
NM_001609.4 splice_donor, intron
NM_001609.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.56
Genes affected
ACADSB (HGNC:91): (acyl-CoA dehydrogenase short/branched chain) Short/branched chain acyl-CoA dehydrogenase(ACADSB) is a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. Substrate specificity is the primary characteristic used to define members of this gene family. The ACADSB gene product has the greatest activity towards the short branched chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts significantly with other 2-methyl branched chain substrates and with short straight chain acyl-CoAs. The cDNA encodes for a mitochondrial precursor protein which is cleaved upon mitochondrial import and predicted to yield a mature peptide of approximately 43.7-KDa. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) 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;
PP5
Variant 10-123037848-G-A is Pathogenic according to our data. Variant chr10-123037848-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203367.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4, Likely_pathogenic=6}. Variant chr10-123037848-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| ACADSB | NM_001609.4 | c.303+1G>A | splice_donor_variant, intron_variant | ENST00000358776.7 | NP_001600.1 | |||
| ACADSB | NM_001330174.3 | c.-3-2618G>A | intron_variant | NP_001317103.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| ACADSB | ENST00000358776.7 | c.303+1G>A | splice_donor_variant, intron_variant | 1 | NM_001609.4 | ENSP00000357873.3 | ||||
| ACADSB | ENST00000368869.8 | c.-3-2618G>A | intron_variant | 2 | ENSP00000357862.4 | |||||
| ACADSB | ENST00000411816.2 | n.320+1G>A | splice_donor_variant, intron_variant | 3 |
Frequencies
GnomAD3 genomes 0.000362 AC: 55AN: 152078Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000251 AC: 63AN: 251174Hom.: 0 AF XY: 0.000287 AC XY: 39AN XY: 135802
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GnomAD4 exome AF: 0.000444 AC: 623AN: 1404192Hom.: 1 Cov.: 26 AF XY: 0.000455 AC XY: 319AN XY: 701580
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GnomAD4 genome 0.000362 AC: 55AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27AN XY: 74284
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:12Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Deficiency of 2-methylbutyryl-CoA dehydrogenase Pathogenic:10
| Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Feb 15, 2024 | The ACADSB c.303+1G>A variant, also known as IVS3+1G>A, has been reported in the homozygous state in two individuals, one individual with a clinical diagnosis of methylbutyryl-CoA dehydrogenase deficiency and the other individual identified by newborn screening (Alfardan J et al., PMID: 20547083). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by eight submitters. This variant is only observed on 77/282,550 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to cause skipping of the exon, leading to an out of frame transcript. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Jul 17, 2014 | This patient is a carrier of a heterozygous pathogenic variant in the ACADSB gene associated with 2-methylbutyrylglycinuria. The ACADSB variant (c.303+1G>A) identified in this patient is located in the first intronic position of the donor splice site and, therefore, meets the criteria for a pathogenic variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2023 | This sequence change affects a donor splice site in intron 3 of the ACADSB 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 ACADSB are known to be pathogenic (PMID: 20547083, 26284228). This variant is present in population databases (rs147936696, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency (PMID: 20547083). This variant is also known as IVS3+1G>A. ClinVar contains an entry for this variant (Variation ID: 203367). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 18, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 01, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 08, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Nov 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2023 | Variant summary: ACADSB c.303+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: One predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00025 in 251174 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00025 vs 0.0011), allowing no conclusion about variant significance. c.303+1G>A has been reported in the literature in two homozygous individuals, an asymptomatic infant and a symptomatic individual, both with Deficiency of 2-methylbutyryl-CoA Dehydrogenase(Alfardan_2010). 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. The following publication have been ascertained in the context of this evaluation (PMID: 20547083). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as pathogenic/likely pathogenic (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Dec 03, 2018 | The ACADSB c.303+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.303+1G>A variant has been reported in one study in which it was found in a homozygous state in two individuals with acyl-CoA dehydrogenase deficiency, oneof whom was symptomatic and the other asymptomatic newborn (Alfardan et al. 2010). Control data are unavailable for this variant, which is reported at a frequency of 0.000931 in the European American population of the Exome Sequencing Project. Based on the potential impact of splice donor variants and the clinical evidence, the c.303+1G>A variant is classified as likely pathogenic for acyl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2024 | The c.303+1G>A variant in ACADSB has been reported in the homozygous state in 2 individual with short/branched chain acyl-CoA dehydrogenase (SBCAD) deficiency; both showed the biochemical phenotype but only one showed clinical symptoms (Alfardan 2010 PMID: 20547083). It has also been reported in the homozygous state in 2 siblings without clinical symptoms (Spedicati 2021 PMID: 33727708). It has been identified in 0.056% (628/1127804) of European (non-Finnish) chromosomes, including 1 homozygote, by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Computational prediction tools and conservation analyses are consistent with pathogenicity. Biallelic loss-of-function of the ACADSB gene is an established disease mechanism in autosomal recessive SBCAD deficiency. SBCAD deficiency results in a biochemical phenotype that be detected from birth; however, the clinical significance of this is unclear. 90% of individuals with SBCAD deficiency have no clinical symptoms, and the remaining 10% may display developmental delay and/or neurological disorders. These 10% of individuals may represent extreme end of the clinical spectrum or coincidental findings (Porta 2019 PMID: 30730842, Alfardan 2010 PMID: 20547083). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive SBCAD deficiency. ACMG/AMP Criteria applied: PVS1, PM3_Supporting. - |
not provided Pathogenic:2Uncertain:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 29, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2023 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 31589614, 20547083, 33727708) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at