rs188094280

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001609.4(ACADSB):c.1159G>A(p.Glu387Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ACADSB
NM_001609.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 9.99

Publications

15 publications found

Variant links:

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACADSB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 10-123053091-G-A is Pathogenic according to our data. Variant chr10-123053091-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 9203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4 link	c.1159G>A	p.Glu387Lys	missense_variant	Exon 10 of 11	ENST00000358776.7	NP_001600.1	P45954-1A0A0S2Z3P9
ACADSB	NM_001330174.3 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 9 of 10		NP_001317103.1	P45954-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACADSB	ENST00000358776.7 link	c.1159G>A	p.Glu387Lys	missense_variant	Exon 10 of 11	1	NM_001609.4	ENSP00000357873.3	P45954-1
ACADSB	ENST00000368869.8 link	c.853G>A	p.Glu285Lys	missense_variant	Exon 9 of 10	2		ENSP00000357862.4	P45954-2
ACADSB	ENST00000541070.1 link	n.331G>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000266

AC:

AN:

251422

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000404

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000230

AC:

336

AN:

1461762

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33472

American (AMR)

AF:

0.000492

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000246

AC:

273

AN:

1111944

Other (OTH)

AF:

0.000397

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000289

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41564

American (AMR)

AF:

0.000719

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000338

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase

Pathogenic:8

Aug 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACADSB c.1159G>A (p.Glu387Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 251422 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADSB causing Deficiency of 2-methylbutyryl-CoA Dehydrogenase (0.00027 vs 0.0011), allowing no conclusion about variant significance. c.1159G>A has been reported in the literature as a biallelic genotype in multiple clinically asymptomatic individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase/Short-branched chain acyl-CoA dehydrogenase (SBCAD) deficiency, determined by elevated blood 2-methylbutyrylcarnitine (C5) and/or urine 2-methylbutyrylglycine (2MBG), often detected initially through newborn screening programs (e.g. Sass_2008, Alfardan_2010, Navarrete_2019, Rossi_2022). These data indicate that the variant is very likely to be associated with disease. When expressed in E. coli, the variant had minimal protein yield and 2% of normal WT activity (Alfardan_2010). The following publications have been ascertained in the context of this evaluation (PMID: 20547083, 30626930, 36147814, 17945527). ClinVar contains an entry for this variant (Variation ID: 9203). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 21, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 07, 2022

New York Genome Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2020

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 387 of the ACADSB protein (p.Glu387Lys). This variant is present in population databases (rs188094280, gnomAD 0.05%). This missense change has been observed in individual(s) with 2-methylbutyryl-coenzyme A dehydrogenase deficiency (PMID: 17945527, 20547083; Invitae). ClinVar contains an entry for this variant (Variation ID: 9203). 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. -

Jan 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 29, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:3

Oct 27, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 20547083); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17945527, 30730842, 34426522, 32778825, 20547083, 36147814) -

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP3, PP4, PM3, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.1

.;L

PhyloP100

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.90

Sift

Benign

0.15

T;T

Sift4G

Benign

0.11

T;T

Polyphen

0.73

.;P

Vest4

0.92

MVP

0.97

MPC

0.36

ClinPred

0.55

GERP RS

5.3

Varity_R

0.64

gMVP

0.96

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over