chr12-120737893-T-C

Position:

chr12-120737893-T-C

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:16

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/exons	MANE	UniProt
ACADS	NM_000017.4 linkuse as main transcript	c.529T>C	p.Trp177Arg	missense_variant	5/10	ENST00000242592.9
ACADS	NM_001302554.2 linkuse as main transcript	c.473-156T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9 linkuse as main transcript	c.529T>C	p.Trp177Arg	missense_variant	5/10	1	NM_000017.4	P1
ACADS	ENST00000411593.2 linkuse as main transcript	c.473-156T>C		intron_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:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 23, 2022	ACMG classification criteria: PS3 supporting, PM3 very strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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). 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: 9499414, 18523805). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 23, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 15, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 02, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 23, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 17, 2022	- -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 22, 2014	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 29, 2022	PP3 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

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 the Genome Aggregation Database (gnomAD), the ACADS c.529T>C alteration was observed in 0.06% (174/282582) of total alleles studied, with a frequency of 0.67% (168/24930) in the African subpopulation. 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) The p.W177R 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

MutationTaster

Benign

1.0

D;D

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