10-123051189-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001609.4(ACADSB):c.1128+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000024 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00027 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACADSB
NM_001609.4 splice_region, intron

Scores

Splicing: ADA: 0.9483

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.38

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.42).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4 link	c.1128+3A>G		splice_region_variant, intron_variant	Intron 9 of 10	ENST00000358776.7	NP_001600.1	P45954-1A0A0S2Z3P9
ACADSB	NM_001330174.3 link	c.822+3A>G		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+3A>G		splice_region_variant, intron_variant	Intron 9 of 10	1	NM_001609.4	ENSP00000357873.3		P45954-1
ACADSB	ENST00000368869.8 link	c.822+3A>G		splice_region_variant, intron_variant	Intron 8 of 9	2		ENSP00000357862.4		P45954-2

Frequencies

GnomAD3 genomes

AF:

0.0000242

AC:

AN:

41316

Hom.:

Cov.:

show subpopulations

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:

0.0000519

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000249

AC:

AN:

24094

AF XY:

0.000146

show subpopulations

Gnomad AFR exome

AF:

0.000776

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000265

AC:

AN:

33912

Hom.:

Cov.:

AF XY:

0.000333

AC XY:

AN XY:

18006

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

736

American (AMR)

AF:

0.00

AC:

AN:

824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1268

East Asian (EAS)

AF:

0.00

AC:

AN:

296

South Asian (SAS)

AF:

0.00

AC:

AN:

4676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1456

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000385

AC:

AN:

23384

Other (OTH)

AF:

0.00

AC:

AN:

1194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000057), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000242

AC:

AN:

41316

Hom.:

Cov.:

AF XY:

0.0000521

AC XY:

AN XY:

19186

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

10488

American (AMR)

AF:

0.00

AC:

AN:

3826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1386

East Asian (EAS)

AF:

0.00

AC:

AN:

3094

South Asian (SAS)

AF:

0.00

AC:

AN:

930

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000519

AC:

AN:

19276

Other (OTH)

AF:

0.00

AC:

AN:

570

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase

Uncertain:2

Apr 01, 2020

Elsea Laboratory, Baylor College of Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

2.4

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.62

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over