10-123009067-G-A

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:4
• Conservation: PhyloP100: 0.0260

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 Benign. Variant got -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 id 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/exons	MANE	UniProt
ACADSB	NM_001609.4	c.38G>A	p.Arg13Lys	missense_variant	1/11	ENST00000358776.7
ACADSB	NM_001330174.3	c.-168G>A		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADSB	ENST00000358776.7	c.38G>A	p.Arg13Lys	missense_variant	1/11	1	NM_001609.4	P1
ACADSB	ENST00000368869.8	c.-164G>A		splice_region_variant, 5_prime_UTR_variant	1/10	2

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

GnomAD3 exomes AF: 0.310 AC: 45435 AN: 146504 Hom.: 7805 AF XY: 0.311 AC XY: 24198 AN XY: 77696

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 SAS exome AF: 0.250

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

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.349

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.439

Gnomad4 NFE exome AF: 0.396

Gnomad4 OTH exome AF: 0.340

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

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.287

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.240

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.393

Gnomad4 OTH AF: 0.316

Alfa AF: 0.371 Hom.: 16642

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

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

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
MutationTaster	Benign	1.0	P;P
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.050
gMVP		0.37

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