rs188094280

Positions:

• chr10-123053091-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.99

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-123053091-G-A is Pathogenic according to our data. Variant chr10-123053091-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-123053091-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADSB	NM_001609.4	c.1159G>A	p.Glu387Lys	missense_variant	10/11	ENST00000358776.7	NP_001600.1
ACADSB	NM_001330174.3	c.853G>A	p.Glu285Lys	missense_variant	9/10		NP_001317103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADSB	ENST00000358776.7	c.1159G>A	p.Glu387Lys	missense_variant	10/11	1	NM_001609.4	ENSP00000357873	P1
ACADSB	ENST00000368869.8	c.853G>A	p.Glu285Lys	missense_variant	9/10	2		ENSP00000357862
ACADSB	ENST00000541070.1	n.331G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152160 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000266 AC: 67 AN: 251422 Hom.: 0 AF XY: 0.000331 AC XY: 45 AN XY: 135876

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 SAS exome AF: 0.0000327

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.: 0 Cov.: 32 AF XY: 0.000237 AC XY: 172 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000246

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152278 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000329 Hom.: 2

Bravo AF: 0.000332

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 06, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 11, 2022	PP3, PP4, PM3, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2023	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) -

Seizure Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

New York Genome Center

Jan 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.1	.;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.61	T
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	D
GERP RS		5.3
Varity_R		0.64
gMVP		0.96

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: rs188094280; hg19: chr10-124812607; COSMIC: COSV62550678;