rs1554873785

Variant names:

• chr10-123047266-A-T
• rs1554873785
• NM_001609.4:c.958A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001609.4(ACADSB):​c.958A>T​(p.Ile320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. I320I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADSB NM_001609.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.486
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17071658).

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.958A>T	p.Ile320Leu	missense	Exon 8 of 11	NP_001600.1	P45954-1
	ACADSB	NM_001330174.3		c.652A>T	p.Ile218Leu	missense	Exon 7 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.958A>T	p.Ile320Leu	missense	Exon 8 of 11	ENSP00000357873.3	P45954-1
	ACADSB	ENST00000908753.1		c.865A>T	p.Ile289Leu	missense	Exon 7 of 10	ENSP00000578812.1
	ACADSB	ENST00000908750.1		c.958A>T	p.Ile320Leu	missense	Exon 8 of 10	ENSP00000578809.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of 2-methylbutyryl-CoA dehydrogenase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	7.7
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.86	L
PhyloP100		0.49
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.41	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.052	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.29		Loss of methylation at K317 (P = 0.1096)
MVP		0.52
MPC		0.056
ClinPred		0.17	T
GERP RS		-4.4
Varity_R		0.20
gMVP		0.62
Mutation Taster		=91/9	polymorphism

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: rs1554873785; hg19: chr10-124806782;