Genetic Variant ACADSB:c.1128+2_1128+3insTA (chr10-123051188-T-TTA) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_001609.4(ACADSB):c.1128+2_1128+3insTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Failed GnomAD Quality Control

Consequence

ACADSB
NM_001609.4 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.38

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4 link	c.1128+2_1128+3insTA		splice_region_variant, intron_variant	Intron 9 of 10	ENST00000358776.7	NP_001600.1	P45954-1A0A0S2Z3P9
ACADSB	NM_001330174.3 link	c.822+2_822+3insTA		splice_region_variant, intron_variant	Intron 8 of 9		NP_001317103.1	P45954-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADSB	ENST00000358776.7 link	c.1128+2_1128+3insTA		splice_region_variant, intron_variant	Intron 9 of 10	1	NM_001609.4	ENSP00000357873.3		P45954-1
ACADSB	ENST00000368869.8 link	c.822+2_822+3insTA		splice_region_variant, intron_variant	Intron 8 of 9	2		ENSP00000357862.4		P45954-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

76456

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

76456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34186

African (AFR)

AF:

0.00

AC:

AN:

18306

American (AMR)

AF:

0.00

AC:

AN:

5184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2230

East Asian (EAS)

AF:

0.00

AC:

AN:

2256

South Asian (SAS)

AF:

0.00

AC:

AN:

1872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

43834

Other (OTH)

AF:

0.00

AC:

AN:

936

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase

Uncertain:1

Jul 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 9 of the ACADSB gene. It does not directly change the encoded amino acid sequence of the ACADSB protein, but it affects a nucleotide within the consensus splice site of the intron. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ACADSB-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Splicing

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over