chr12-120737893-T-C

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 9P and 1B. PP3PP5_Very_StrongBP4

The NM_000017.4(ACADS):c.529T>C(p.Trp177Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000344 in 1,614,116 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0018 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 3 hom. )

Consequence

ACADS
NM_000017.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20

Conservation

PhyloP100: 7.65

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 Likely_pathogenic. Variant got 8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 12-120737893-T-C is Pathogenic according to our data. Variant chr12-120737893-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.16962817). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4 link	c.529T>C	p.Trp177Arg	missense_variant	Exon 5 of 10	ENST00000242592.9	NP_000008.1	P16219E5KSD5
ACADS	NM_001302554.2 link	c.473-156T>C		intron_variant	Intron 4 of 9		NP_001289483.1	P16219E9PE82B4DUH1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ACADS	ENST00000242592.9 link	c.529T>C	p.Trp177Arg	missense_variant	Exon 5 of 10	1	NM_000017.4	ENSP00000242592.4	P16219
ACADS	ENST00000411593.2 link	c.473-156T>C		intron_variant	Intron 4 of 9	2		ENSP00000401045.2	E9PE82
ACADS	ENST00000539690.1 link	n.*88T>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

279

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00630

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

251254

Hom.:

AF XY:

0.000317

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00665

Gnomad AMR exome

AF:

0.000145

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000188

AC:

275

AN:

1461840

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00711

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.00184

AC:

280

AN:

152276

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00630

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000445

Hom.:

Bravo

AF:

0.00206

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000552

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:15

Aug 23, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACADS c.529T>C (p.Trp177Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) 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 0.00045 in 251254 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADS causing Deficiency Of Butyryl-CoA Dehydrogenase, allowing no conclusion about variant significance. c.529T>C has been reported in the literature in multiple individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (example: Gregerson_1998, Koeberl_2003, Waisbren_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Gregerson_1998). The following publications have been ascertained in the context of this evaluation (PMID: 12736383, 18676165, 9499414). ClinVar contains an entry for this variant (Variation ID: 3828). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 04, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_000017.2:c.529T>C in the ACADS gene has an allele frequency of 0.007 in Africa subpopulation in the gnomAD database. Functional studies demonstrate that c.529T>C has affected aggregation and abolishes enzymatic activity of the encoded protein (PMID: 9499414; 18523805). It was detected in multiple individuals with autosomal recessive Deficiency of butyryl-CoA dehydrogenase, two homozygous c.529T>C (p.Trp177Arg), compound heterozygous with c.988C>T (p.Arg330Cys) (PMID: 22241096; 18676165; 12736383). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3_Strong; PP4. -

Oct 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Trp177Arg variant in ACADS has been reported in the homozygous state in at least 7 individuals and in the compound heterozygous state in 11 individuals with short chain acyl-CoA dehydrogenase deficiency (SCADD) that was detected from biochemical evaluations; however, many of these individuals were asymptomatic at the time of study (Gregersen 1998 PMID: 9499414, Koeberl 2003 PMID: 12736383, Waisbren 2008 PMID: 18676165, Pena 2012 PMID: 22241096, Maguolo 2020 PMID: 32793418, Sadat 2020 PMID: 31813752). It has also been reported by other clinical laboratories in ClinVar (Variation ID 3828) and has been identified in 0.6% (261/41434) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), including 3 homozygotes, which is consistent with the frequency and manifestation of SCADD in the generation population. In vitro functional studies provide evidence that this variant reduces enzyme activity (Gregersen 1998 PMID: 9499414) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive SCADD. ACMG/AMP Criteria applied: PM3_Strong, PP3, PS3_Supporting, PP4. -

May 22, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM3_Very Strong -

Aug 22, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 177 of the ACADS protein (p.Trp177Arg). This variant is present in population databases (rs57443665, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with SCAD deficiency (PMID: 9499414, 12736383, 18676165, 22241096). ClinVar contains an entry for this variant (Variation ID: 3828). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 9499414, 18523805). For these reasons, this variant has been classified as Pathogenic. -

Dec 10, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -

Jan 24, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (T>C) at position 529 of the coding sequence of the ACADS gene that results in a tryptophan to arginine amino acid change at residue 177 of the acyl-CoA dehydrogenase short chain protein. This is a previously reported variant (ClinVar 3828) that has been observed in multiple individuals affected by short-chain acyl-CoA dehydrogenase deficiency when in the homozygous or compound heterozygous state (PMID: 18523805, 18676165, 22241096, 23798014, 32793418, 9499414). This variant is present in 393 of 403412 alleles (0.0974%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this tryptophan to arginine amino acid change would be damaging, and the Trp177 residue at this position is highly conserved across the vertebrate species examined. The protein generated from this variant exhibits nearly no short-chain specific acyl-CoA dehydrogenase activity in a ferricenium ion-based assay (PMID: 9499414) and exhibits evidence of misfolding within a mouse mitochondrial system (PMID: 18523805). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: BS1, PM3, PP2, PP3, PP5, PS3 -

Oct 15, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The homozygous c.529T>C (p.Trp177Arg) variant identified in the ACADS gene substitutes a well conserved Tryptophan for Arginine at amino acid177/413 (exon 5/10). This variant is found with appreciable frequency in gnomAD (279 heterozygotes, 3 homozygotes; allele frequency:1.83e-3). In silico algorithms predict it to be Damaging (SIFT; score:0.00) and Pathogenic (REVEL; score:0.957) to the function of the canonical transcript. This variant is reported as LikelyPathogenic/Pathogenic in ClinVar (VarID:3828) and has been reported in many individuals in the literature with biochemical findings consistent with SCADD [PMID:9499414, 18523805, 23798014, others]. Functional studies suggest it significantly impairs enzyme activity [PMID:9499414]. The homozygous c.529T>C(p.Trp177Arg) variant identified in the ACADS gene is reported as Pathogenic. -

not provided

Pathogenic:3

Jan 06, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3 -

Nov 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency using alternative nomenclature (Gregersen et al., 1998); Functional analysis found that this variant is associated with significantly reduced enzyme activity compared to wild-type (Gregersen et al., 1998); 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: 18523805, 12736383, 28263315, 16546179, 18676165, 22241096, 23798014, 22424739, 9499414, 31589614, 31813752, 32778825) -

ACADS-related disorder

Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADS c.529T>C variant is predicted to result in the amino acid substitution p.Trp177Arg. This variant, which has also been described as W153R, has been reported in the homozygous or compound heterozygous state in multiple patients with autosomal recessive short chain acyl-CoA dehydrogenase deficiency, although it should be noted that not all reported patients were clinically symptomatic (Gregersen et al. 1998. PubMedID: 9499414; Koeberl et al. 2003. PubMedID: 12736383; Pedersen et al. 2008. PubMed ID: 18523805; Waisbren et al. 2008. PubMed ID: 18676165; Waisbren et al. 2013. PubMed ID: 23798014). In experimental studies, the p.Trp177Arg substitution lead to near complete loss of enzyme activity, disrupted tetramer formation, and increased aggregation tendency (Gregersen et al. 1998. PubMedID: 9499414; Pedersen et al. 2008. PubMed ID: 18523805). In summary, we classify this variant as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jul 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.529T>C (p.W177R) alteration is located in exon 5 (coding exon 5) of the ACADS gene. This alteration results from a T to C substitution at nucleotide position 529, causing the tryptophan (W) at amino acid position 177 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.062% (174/282582) total alleles studied. The highest observed frequency was 0.674% (168/24930) of African alleles. This alteration has been reported as homozygous and compound heterozygous in multiple individuals with biochemical diagnoses of short-chain acyl-CoA dehydrogenase deficiency (Waisbren, 2008; Pedersen, 2008; Gregersen, 1998; Koeberl, 2003; Pena, 2012; Maguolo, 2020). This amino acid position is highly conserved in available vertebrate species. In a ferricenium ion-based enzyme activity assay, this alteration had no detectable activity above background (Gregersen, 1998) This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.17

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.8

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-8.8

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.99

MutPred

0.93

Gain of disorder (P = 0.0062);

MVP

1.0

MPC

1.0

ClinPred

0.98

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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