rs387906409

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001609.4(ACADSB):c.1228G>A(p.Gly410Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 1,544,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G410V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ACADSB
NM_001609.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 9.97

Publications

4 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_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 10-123053160-G-A is Pathogenic according to our data. Variant chr10-123053160-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9199.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADSB	NM_001609.4 link	c.1228G>A	p.Gly410Ser	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000358776.7	NP_001600.1
ACADSB	NM_001330174.3 link	c.922G>A	p.Gly308Ser	missense_variant, splice_region_variant	Exon 9 of 10		NP_001317103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ACADSB	ENST00000358776.7 link	c.1228G>A	p.Gly410Ser	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_001609.4	ENSP00000357873.3
ACADSB	ENST00000368869.8 link	c.922G>A	p.Gly308Ser	missense_variant, splice_region_variant	Exon 9 of 10	2		ENSP00000357862.4
ACADSB	ENST00000541070.1 link	n.400G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000110

AC:

AN:

91058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000434

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

GnomAD2 exomes

AF:

0.0000295

AC:

AN:

237360

AF XY:

0.0000466

show subpopulations

Gnomad AFR exome

AF:

0.0000658

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000895

AC:

AN:

1453070

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33290

American (AMR)

AF:

0.0000224

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39618

South Asian (SAS)

AF:

0.000140

AC:

AN:

85926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104366

Other (OTH)

AF:

0.00

AC:

AN:

60042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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

AF:

0.0000110

AC:

AN:

91058

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

42932

show subpopulations

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

African (AFR)

AF:

0.0000434

AC:

AN:

23044

American (AMR)

AF:

0.00

AC:

AN:

7324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2276

East Asian (EAS)

AF:

0.00

AC:

AN:

3194

South Asian (SAS)

AF:

0.00

AC:

AN:

1972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4832

Middle Eastern (MID)

AF:

0.00

AC:

AN:

198

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

46316

Other (OTH)

AF:

0.00

AC:

AN:

1178

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), 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

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of 2-methylbutyryl-CoA dehydrogenase

Pathogenic:2

Jun 28, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACADSB c.1228G>A (p.Gly410Ser) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. This was confirmed via cDNA sequencing of a homozygous patient, which showed that the variant causes skipping of exon 10 (Andresen_2000). The variant allele was found at a frequency of 2.9e-05 in 237360 control chromosomes (gnomAD). c.1228G>A has been reported in the literature in a Pakistani family with two homozygous individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase (Andresen_2000). These data indicate that the variant is likely to be associated with disease. Although the variant did not cause absence of the protein through nonsense mediated decay, fibroblasts from a homozygous patient showed less than 10% residual activity when compared to control fibroblasts (Andresen_2000). The following publication have been ascertained in the context of this evaluation (PMID: 11013134). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 01, 2000

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

.;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

0.87

MutationAssessor

Benign

1.6

.;L

PhyloP100

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.026

D;D

Sift4G

Benign

0.14

T;D

Polyphen

1.0

.;D

Vest4

0.66

MutPred

0.47

.;Loss of sheet (P = 0.0817);

MVP

0.97

MPC

0.36

ClinPred

0.69

GERP RS

5.3

Varity_R

0.96

gMVP

0.95

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.90

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.90

Position offset: 0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over