rs121908003

chr12-120727115-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_000017.4(ACADS):c.136C>T(p.Arg46Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R46Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.95

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 Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-120727116-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1002010.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

PP5

Variant 12-120727115-C-T is Pathogenic according to our data. Variant chr12-120727115-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-120727115-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.136C>T	p.Arg46Trp	missense_variant	2/10	ENST00000242592.9
ACADS	NM_001302554.2 linkuse as main transcript	c.136C>T	p.Arg46Trp	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
ACADS	ENST00000242592.9 linkuse as main transcript	c.136C>T	p.Arg46Trp	missense_variant	2/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.136C>T	p.Arg46Trp	missense_variant	2/10	2
ACADS	ENST00000539690.1 linkuse as main transcript	n.248C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251496

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

106

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000916

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000112

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000999

Hom.:

Bravo

AF:

0.000125

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:9

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 16, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the ACADS protein (p.Arg46Trp). This variant is present in population databases (rs121908003, gnomAD 0.08%). This missense change has been observed in individuals with SCAD deficiency (PMID: 1692038, 18523805, 28454995). This variant is also known as R22W. ClinVar contains an entry for this variant (Variation ID: 3825). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADS function (PMID: 9582344, 14506246). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 14506246, 9582344). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003825). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1692038, 28454995). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1989	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 11, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2024	Variant summary: ACADS c.136C>T (p.Arg46Trp) results in a non-conservative amino acid change located in the acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251496 control chromosomes (gnomAD). c.136C>T has been reported in the literature as a biallelic genotype in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (e.g. Naito_1990, Pedersen_2008, Alfares_2017). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (Corydon_1998, Pedersen_2003). The results showed that the variant primarily existed as an insoluble protein, likely due to protein misfolding, and resulted in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 9582344, 1692038, 18523805, 14506246). ClinVar contains an entry for this variant (Variation ID: 3825). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 03, 2022	- -

ACADS-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2023

The ACADS c.136C>T variant is predicted to result in the amino acid substitution p.Arg46Trp. This variant was previously referred to as R22W in the literature. This variant has been reported in the homozygous or compound heterozygous state in patients with short chain acyl-CoA-dehydrogenase deficiency (Corydon et al. 1998. PubMed ID: 9582344; Alfares et al. 2017. PubMed ID: 28454995; Messina M et al. 2020. PubMed ID: 33239584). In experimental studies, the p.Arg46Trp substitution has been shown to result in decreased enzyme activity as well as affecting protein folding, increased protein aggregation, and more rapid degradation than wild-type (Corydon et al. 1998. PubMed ID: 9582344; Pedersen et al. 2003. PubMed ID: 14506246). The c.136C>T variant has been reported at a maximum allele frequency of ~0.08% in a large population database, indicating it is rare in the general population (http://gnomad-old.broadinstitute.org/variant/12-121164918-C-T). In summary, we classify this variant as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2022

Published functional studies demonstrate increased protein degradation, reduced tetramer formation, increased aggregation tendency, and increased chaperone retention (Corydon et al., 1998; Pedersen et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 14506246, 28516284, 18523805, 1692038, 22424739, 18676165, 28454995, 34426522, 31589614, 31980526, 33239584, 32778825, 9582344) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.7

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.71

MVP

1.0

MPC

0.77

ClinPred

0.97

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.90

gMVP

0.91

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