chr10-123040605-C-T

Variant names:

• chr10-123040605-C-T
• rs58639322
• NM_001609.4:c.443C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PS3 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). ClinVar reports functional evidence for this variant: "SCV000645153: Experimental studies have shown that this missense change affects ACADSB function (PMID:20547083)." and additional evidence is available in ClinVar.

• 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:13 U:2
• Conservation: PhyloP100: -0.280
• Publications: 16 publications found

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]

ACADSB Gene-Disease associations (from GenCC):

• 2-methylbutyryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000645153: Experimental studies have shown that this missense change affects ACADSB function (PMID: 20547083).; SCV000915461: "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)."; SCV002766172: When the variant was expressed in E. coli, the variant had minimal protein yield and 2.8% normal activity (Alfardan_2010).; SCV005418668: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006581550: Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 20547083).; SCV001247458: PS3:Supporting; SCV003741195: "In E. coli with this variant, enzyme activity was reduced to 2.8% of wild type activity levels (Alfardan, 2010)."
• 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 VariationId is 9202.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADSB	NM_001609.4	MANE Select	c.443C>T	p.Thr148Ile	missense	Exon 4 of 11	NP_001600.1	P45954-1
	ACADSB	NM_001330174.3		c.137C>T	p.Thr46Ile	missense	Exon 3 of 10	NP_001317103.1	P45954-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADSB	ENST00000358776.7	TSL:1 MANE Select	c.443C>T	p.Thr148Ile	missense	Exon 4 of 11	ENSP00000357873.3	P45954-1
	ACADSB	ENST00000908753.1		c.443C>T	p.Thr148Ile	missense	Exon 4 of 10	ENSP00000578812.1
	ACADSB	ENST00000908750.1		c.443C>T	p.Thr148Ile	missense	Exon 4 of 10	ENSP00000578809.1

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

GnomAD2 exomes AF: 0.000831 AC: 209 AN: 251424 AF XY: 0.00101

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 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

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00267 AC: 230 AN: 86254

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53418

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000728 AC: 810 AN: 1111976

Other (OTH) AF: 0.000927 AC: 56 AN: 60394

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

African (AFR) AF: 0.000193 AC: 8 AN: 41558

American (AMR) AF: 0.000327 AC: 5 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4816

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00101 AC: 69 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000809 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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
11	1	-	Deficiency of 2-methylbutyryl-CoA dehydrogenase (12)
1	1	-	not provided (2)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Uncertain	0.70	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.058	N
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.28
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.58
Sift	Benign	0.35	T
Sift4G	Benign	0.42	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
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

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