12-120725925-C-G

Position:

chr12-120725925-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000017.4(ACADS):c.40C>G(p.Arg14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000927 in 1,553,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.209

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14983991).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.40C>G	p.Arg14Gly	missense_variant	1/10	ENST00000242592.9
ACADS	NM_001302554.2 linkuse as main transcript	c.40C>G	p.Arg14Gly	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ACADS	ENST00000242592.9 linkuse as main transcript	c.40C>G	p.Arg14Gly	missense_variant	1/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.40C>G	p.Arg14Gly	missense_variant	1/10	2
ACADS	ENST00000539690.1 linkuse as main transcript	n.152C>G		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151890

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:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000135

AC:

AN:

155320

Hom.:

AF XY:

0.0000923

AC XY:

AN XY:

86652

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:

0.000315

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000942

AC:

132

AN:

1401224

Hom.:

Cov.:

AF XY:

0.0000879

AC XY:

AN XY:

694212

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:

0.000118

Gnomad4 OTH exome

AF:

0.0000513

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151890

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74176

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:

0.0000943

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000379

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000632

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 14 of the ACADS protein (p.Arg14Gly). This variant is present in population databases (rs542140065, gnomAD 0.03%). 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: 649343). This variant has not been reported in the literature in individuals affected with ACADS-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.48

T;T

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.69

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.15

T;T

MetaSVM

Uncertain

0.080

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.028

D;D

Sift4G

Uncertain

0.047

D;T

Polyphen

0.0

B;B

Vest4

0.23

MVP

0.83

MPC

0.25

ClinPred

0.13

GERP RS

0.89

Varity_R

0.16

gMVP

0.52

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