rs58639322

chr10-123040605-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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: {Pathogenic=4, Likely_pathogenic=3, Uncertain_significance=3}. Variant chr10-123040605-C-T is described in Lovd as [Likely_pathogenic].

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: 106 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000831 AC: 209 AN: 251424 Hom.: 0 AF XY: 0.00101 AC XY: 137 AN XY: 135878

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00268

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000835

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000787 AC: 1150 AN: 1461828 Hom.: 2 Cov.: 32 AF XY: 0.000902 AC XY: 656 AN XY: 727216

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00267

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.000728

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000766 AC XY: 57 AN XY: 74440

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000808 Hom.: 0

Bravo AF: 0.000499

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase Pathogenic:6 Uncertain:2

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	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
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, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
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:1 Uncertain: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Uncertain	0.12
Cadd	Benign	1.2
Dann	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.000047	A;A
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.58
Sift	Benign	0.35	T;D
Sift4G	Benign	0.42	T;T
Polyphen		0.63	.;P
Vest4		0.33
MVP		0.80
MPC		0.19
ClinPred		0.12	T
GERP RS		-11
Varity_R		0.42
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs58639322; hg19: chr10-124800121; COSMIC: COSV100715108;