rs58639322
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_001609.4(ACADSB):c.443C>T(p.Thr148Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,614,094 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00070 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00079 ( 2 hom. )
Consequence
ACADSB
NM_001609.4 missense
NM_001609.4 missense
Scores
2
6
9
Clinical Significance
Conservation
PhyloP100: -0.280
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 Likely_benign. Variant got -3 ACMG points.
PP5
?
Variant 10-123040605-C-T is Pathogenic according to our data. Variant chr10-123040605-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9202.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=4, Likely_pathogenic=3}. Variant chr10-123040605-C-T is described in Lovd as [Likely_pathogenic].
BS2
?
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ACADSB | NM_001609.4 | c.443C>T | p.Thr148Ile | missense_variant | 4/11 | ENST00000358776.7 | |
ACADSB | NM_001330174.3 | c.137C>T | p.Thr46Ile | missense_variant | 3/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ACADSB | ENST00000358776.7 | c.443C>T | p.Thr148Ile | missense_variant | 4/11 | 1 | NM_001609.4 | P1 | |
ACADSB | ENST00000368869.8 | c.137C>T | p.Thr46Ile | missense_variant | 3/10 | 2 | |||
ACADSB | ENST00000411816.2 | n.460C>T | non_coding_transcript_exon_variant | 4/4 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000697 AC: 106AN: 152148Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000831 AC: 209AN: 251424Hom.: 0 AF XY: 0.00101 AC XY: 137AN XY: 135878
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GnomAD4 exome AF: 0.000787 AC: 1150AN: 1461828Hom.: 2 Cov.: 32 AF XY: 0.000902 AC XY: 656AN XY: 727216
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Deficiency of 2-methylbutyryl-CoA dehydrogenase Pathogenic:6Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2022 | Variant summary: ACADSB c.443C>T (p.Thr148Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00083 in 251424 control chromosomes (gnomAD). c.443C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Deficiency Of 2-Methylbutyryl Dehydrogenase (e.g. Korman_2005, Sass_2008, Porta_2019). These data indicate that the variant is very likely to be associated with disease. When the variant was expressed in E. coli, the variant had minimal protein yield and 2.8% normal activity (Alfardan_2010). Seven ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, one as likely pathogenic, and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2008 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 26, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The ACADSB c.443C>T (p.Thr148Ile) missense variant has been reported in at least three studies in which it is found in a total of six patients with acyl-CoA dehydrogenase, short/branched chain deficiency, including in three, of whom two are siblings, who carried the variant in a homozygous state, and three, of whom two are siblings, who carried the variant in a compound heterozygous state (Korman et al. 2005; Sass et al. 2008; Alfardan et al. 2010). The p.Thr148Ile variant was not detected in 92 control chromosomes and is reported at a frequency of 0.0023 in the South Asian population of the Exome Aggregation Consortium. In vitro expression in E. coli found that the p.Thr148Ile variant protein had almost undetectable activity compared to wild type (Alfardan et al. 2010). It should be noted that some individuals with this disorder may remain asymptomatic throughout life. Based on the evidence, the p.Thr148Ile variant is classified as pathogenic for acyl-CoA dehydrogenase, short/branched chain 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 | Invitae | Jan 10, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 148 of the ACADSB protein (p.Thr148Ile). This variant is present in population databases (rs58639322, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with SBCAD deficiency (PMID: 15615815, 17945527, 20547083, 30730842). ClinVar contains an entry for this variant (Variation ID: 9202). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACADSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Oct 14, 2019 | The variant was confirmed as compound heterozygous with a likely pathogenic variant (NM_001609.3: c.1228+2T>C). - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Apr 08, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | ACADSB: PM3:Strong, PM2, PP4:Moderate, PS3:Supporting - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2021 | The c.443C>T (p.T148I) alteration is located in exon 4 (coding exon 4) of the ACADSB gene. This alteration results from a C to T substitution at nucleotide position 443, causing the threonine (T) at amino acid position 148 to be replaced by an isoleucine (I). This variant has been reported in individuals with biochemical evidence of 2-methylbutyrylglycinuria in both the homozygous and compound heterozygous state; however, most were reported as clinically asymptomatic (Korman, 2005; Sass, 2008; Alfardan, 2010; Porta, 2019). One individual presented with a history of metabolic acidosis and coma during illness (Porta, 2019). In E. coli with this variant, enzyme activity was reduced to 2.8% of wild type activity levels (Alfardan, 2010). The in silico prediction for the p.T148I alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Uncertain
Sift
Benign
T;D
Sift4G
Benign
T;T
Polyphen
0.63
.;P
Vest4
MVP
MPC
0.19
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at