rs137852649

Positions:

chr10-123043127-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001609.4(ACADSB):c.763C>T(p.Leu255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ACADSB
NM_001609.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.07

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-123043127-C-T is Pathogenic according to our data. Variant chr10-123043127-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9200.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-123043127-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADSB	NM_001609.4 linkuse as main transcript	c.763C>T	p.Leu255Phe	missense_variant	6/11	ENST00000358776.7	NP_001600.1
ACADSB	NM_001330174.3 linkuse as main transcript	c.457C>T	p.Leu153Phe	missense_variant	5/10		NP_001317103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADSB	ENST00000358776.7 linkuse as main transcript	c.763C>T	p.Leu255Phe	missense_variant	6/11	1	NM_001609.4	ENSP00000357873	P1	P45954-1
ACADSB	ENST00000368869.8 linkuse as main transcript	c.457C>T	p.Leu153Phe	missense_variant	5/10	2		ENSP00000357862		P45954-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152130

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251470

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1461734

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000322

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2020	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects ACADSB protein function (PMID: 10832746). This variant has been observed in individual(s) with SBCAD deficiency (PMID: 10832746, 16317551, 17945527). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9200). This variant is present in population databases (rs137852649, ExAC 0.003%). This sequence change replaces leucine with phenylalanine at codon 255 of the ACADSB protein (p.Leu255Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2006	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;D

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.21

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.2

.;M

MutationTaster

Benign

0.43

A;A

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.95

.;P

Vest4

0.34

MVP

0.88

MPC

0.13

ClinPred

0.50

GERP RS

-1.6

Varity_R

0.61

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over