12-120739440-C-T

Position:

chr12-120739440-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000017.4(ACADS):c.1231C>T(p.Arg411Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000994 in 1,609,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.87

Variant links:

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACADS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.1231C>T	p.Arg411Trp	missense_variant	10/10	ENST00000242592.9
ACADS	NM_001302554.2 linkuse as main transcript	c.1219C>T	p.Arg407Trp	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9 linkuse as main transcript	c.1231C>T	p.Arg411Trp	missense_variant	10/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.1219C>T	p.Arg407Trp	missense_variant	10/10	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000209

AC:

AN:

239314

Hom.:

AF XY:

0.0000228

AC XY:

AN XY:

131532

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000226

Gnomad SAS 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:

0.00000824

AC:

AN:

1457182

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000756

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 03, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 28, 2021	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADS protein function. ClinVar contains an entry for this variant (Variation ID: 557652). This missense change has been observed in individual(s) with short chain acyl-CoA dehydrogenase deficiency (PMID: 18523805). This variant is present in population databases (rs369416846, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 411 of the ACADS protein (p.Arg411Trp). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.24

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.5

N;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.99

D;.

Vest4

0.81

MVP

1.0

MPC

0.68

ClinPred

0.93

GERP RS

3.9

Varity_R

0.58

gMVP

0.64

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