NM_001609.4:c.38G>A

Variant names:

• chr10-123009067-G-A
• rs12263012
• NM_001609.4:c.38G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001609.4(ACADSB):​c.38G>A​(p.Arg13Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,546,378 control chromosomes in the GnomAD database, including 106,321 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R13S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (7982 hom., cov: 32)
  • Exomes 𝑓: 0.37 (98339 hom.)
• Consequence: ACADSB NM_001609.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0260
• Publications: 28 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.1785836E-4).
• BP6: Variant 10-123009067-G-A is Benign according to our data. Variant chr10-123009067-G-A is described in ClinVar as Benign. ClinVar VariationId is 299068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.389 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4	c.38G>A	p.Arg13Lys	missense_variant	Exon 1 of 11	ENST00000358776.7	NP_001600.1
ACADSB	NM_001330174.3	c.-168G>A		5_prime_UTR_variant	Exon 1 of 10		NP_001317103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADSB	ENST00000358776.7	c.38G>A	p.Arg13Lys	missense_variant	Exon 1 of 11	1	NM_001609.4	ENSP00000357873.3
ACADSB	ENST00000368869.8	c.-164G>A		splice_region_variant	Exon 1 of 10	2		ENSP00000357862.4
ACADSB	ENST00000368869.8	c.-164G>A		5_prime_UTR_variant	Exon 1 of 10	2		ENSP00000357862.4

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45237 AN: 151960 Hom.: 7985 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.393

Gnomad OTH AF: 0.317

GnomAD2 exomes AF: 0.310 AC: 45435 AN: 146504 AF XY: 0.311

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.346

Gnomad EAS exome AF: 0.116

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.392

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.369 AC: 513968 AN: 1394300 Hom.: 98339 Cov.: 45 AF XY: 0.365 AC XY: 251287 AN XY: 687992

African (AFR) AF: 0.115 AC: 3617 AN: 31582

American (AMR) AF: 0.264 AC: 9435 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 8781 AN: 25166

East Asian (EAS) AF: 0.121 AC: 4321 AN: 35728

South Asian (SAS) AF: 0.253 AC: 20038 AN: 79198

European-Finnish (FIN) AF: 0.439 AC: 19688 AN: 44840

Middle Eastern (MID) AF: 0.268 AC: 1477 AN: 5516

European-Non Finnish (NFE) AF: 0.396 AC: 426936 AN: 1078652

Other (OTH) AF: 0.340 AC: 19675 AN: 57932

GnomAD4 genome AF: 0.297 AC: 45241 AN: 152078 Hom.: 7982 Cov.: 32 AF XY: 0.297 AC XY: 22051 AN XY: 74316

African (AFR) AF: 0.125 AC: 5183 AN: 41548

American (AMR) AF: 0.287 AC: 4395 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3466

East Asian (EAS) AF: 0.124 AC: 638 AN: 5130

South Asian (SAS) AF: 0.240 AC: 1159 AN: 4826

European-Finnish (FIN) AF: 0.461 AC: 4875 AN: 10578

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.393 AC: 26721 AN: 67916

Other (OTH) AF: 0.316 AC: 666 AN: 2110

Alfa AF: 0.359 Hom.: 21084

Bravo AF: 0.276

TwinsUK AF: 0.399 AC: 1481

ALSPAC AF: 0.399 AC: 1537

ESP6500AA AF: 0.118 AC: 388

ESP6500EA AF: 0.362 AC: 2125

ExAC AF: 0.261 AC: 6206

Asia WGS AF: 0.173 AC: 604 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase Benign:3

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17143180) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.084	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0032	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.00042	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.026
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.17
Sift	Benign	0.73	T
Sift4G	Benign	0.51	T
Polyphen		0.012	B
Vest4		0.048
MPC		0.058
ClinPred		0.0014	T
GERP RS		0.82
PromoterAI		0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.37
Mutation Taster		=95/5	polymorphism (auto)

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: rs12263012; hg19: chr10-124768583; COSMIC: COSV62551234; COSMIC: COSV62551234;