rs147559466

Positions:

chr1-75732652-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_000016.6(ACADM):c.127G>A(p.Glu43Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,494 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 5 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9B:2

Conservation

PhyloP100: 7.34

Variant links:

Genes affected

ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACADM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a helix (size 15) in uniprot entity ACADM_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000016.6

BP4

Computational evidence support a benign effect (MetaRNN=0.010578901).

BS2

High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.127G>A	p.Glu43Lys	missense_variant	3/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9 linkuse as main transcript	c.127G>A	p.Glu43Lys	missense_variant	3/12	1	NM_000016.6	P4	P11310-1

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000435

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00293

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00329

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00206

AC:

517

AN:

251212

Hom.:

AF XY:

0.00207

AC XY:

281

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.000434

Gnomad AMR exome

AF:

0.000983

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.00249

Gnomad NFE exome

AF:

0.00294

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00245

AC:

3580

AN:

1461308

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1774

AN XY:

726980

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00101

Gnomad4 ASJ exome

AF:

0.00429

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000754

Gnomad4 FIN exome

AF:

0.00255

Gnomad4 NFE exome

AF:

0.00276

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00207

AC:

315

AN:

152186

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.000434

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00662

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00293

Gnomad4 NFE

AF:

0.00328

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00270

Hom.:

Bravo

AF:

0.00165

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00224

AC:

272

EpiCase

AF:

0.00294

EpiControl

AF:

0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Uncertain:5Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 07, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous missense variant, NM_000016.4(ACADM):c.127G>A, has been identified in exon 3 of 12 of the ACADM gene. The variant is predicted to result in a minor amino acid change from Glu to Lys at position 43 of the protein (NP_000007.1(ACADM):p.(Glu43Lys)). The Glu residue at this position has low conservation (100 vertebrates, UCSC), and is located within the Acyl-CoA dehydrogenase, N-terminal domain functional domain. In-silico predictions of pathogenicity for this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a frequency of 0.2% (590 heterozygotes, 2 homozygotes). An alternative residue change has been reported in the gnomAD database at a frequency of 0.0004%. The variant has been previously reported with conflicting interpretations of pathogenicity (ClinVar). It is argued that this variant's first reports were in a prospective newborn screening in asymptomatic individuals with altered biochemical results (Smith, E.H. et al., 2010). However, later reports demonstrate that this variant has not been identified in patients, but rather in unaffected individuals with no significant biochemical phenotype (Smith, E.H. et al., 2010; Sturm, M. et al., 2012). After following up individiuals identified with this variant, a recent report reclassifies it from pathogenic to benign due to high population frequency and lack of clinical correlation (Garber, K.B. et al., 2016). Additionally, functional analysis are inconclusive regarding biological significance. Overall it seems to have a mild effect in vitro, biochemically and clinically (Koster, K.L. et al., 2014). Sturm et al. (2010) suggests this variant is a innocuous polymorphism as oxidation residual activity was in the range of 31-60% for compound heterozygous, however the risk for disease should be below 20%. Based on the information available at the time of curation, this variant has been classified as LIKELY BENIGN. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 26, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 43 of the ACADM protein (p.Glu43Lys). This variant is present in population databases (rs147559466, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild medium-chain acyl-CoA dehydrogenase deficiency (PMID: 20036593, 20434380, 22166308, 23028790; Invitae). ClinVar contains an entry for this variant (Variation ID: 92257). 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 not expected to disrupt ACADM protein function. Experimental studies have shown that this missense change does not substantially affect ACADM function (PMID: 23028790, 24966162). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 17, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.127G>A(p.Glu43Lys) in ACADM gene has been observed in individual(s) with mild medium-chain acyl-CoA dehydrogenase deficiency (Sturm et. al., 2012; Oerton et. al., 2011). Experimental studies have shown that this missense change does not substantially affect ACADM function (Koster et. al., 2014). The observed variant has allele frequency of 0.2% in gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely benign / Pathogenic / Uncertain Significance (multiple submissions). The amino acid change p.Glu43Lys in ACADM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Glu at position 43 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to confirm the pathogenicity of the variant. For these reasons, this variant has been classified as Uncertain Significance (VUS). -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Pathogenic:3Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ACADM: PM2, PM3, BS2 -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 30, 2023	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 17, 2023

Variant summary: ACADM c.127G>A (p.Glu43Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251212 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.0021 vs 0.0054), allowing no conclusion about variant significance. This variant has been reported in several subjects during newborn screening programs in compound heterozygous with another pathogenic variant c.985A>G (Example: Smith_2010, Sturm_2012, Catarzi_2013, Navarrete_ 2019, Jager_ 2019, Anderson_ 2019, Alcaide_2022 etc.). However, they were biochemically indistinguishable from MCAD carriers, suggesting this variant is likely innocuous. In addition, asymptomatic father of an MCAD deficient child, homozygous for the c.985A>G mutation, was compound heterozygous for a pathogenic variant (Sturm_2012). Enzymatic measurement in lymphocytes from a subject who was compound heterozygous for this variant and c.985A>G showed 56% of normal activity, clearly in the range of proven heterozygotes that do not have a risk of symptomatic disease, unless in a situation of possible synergistic heterozygosity (Sturm_2012). Functional study (Koster_2014) showed variant with comparable to WT specificity to substrates C8-CoA and C12-CoA, and ~60% WT level of specificity to substrate C10-coA and the residual activity of variant was improved by co-overexpression with molecular chaperones and variant to >100% of WT level. 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, VUS (n=7), Pathogenic (n=2) and Likely Benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 21, 2020

ACMG classification criteria: PM3, PP3, BS1 -

ACADM-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2023

The ACADM c.127G>A variant is predicted to result in the amino acid substitution p.Glu43Lys. The c.127G>A variant has been reported in a large population database at an allele frequency of up to 0.44%, which is relatively high for a pathogenic variant (http://gnomad.broadinstitute.org/variant/1-76198337-G-A). It has also been reported in patients with suspected medium chain acyl-CoA dehydrogenase deficiency (MCADD), though it is unclear whether the c.127G>A variant causes a mild biochemical phenotype or is an innocuous, benign variant (McKinney et al 2004. PubMed ID: 15171998; Sturm et al. 2012. PubMed ID: 23028790; Koster et al. 2014. PubMed ID: 24966162). It has been observed in individuals with the common c.985A>G (p.Lys304Glu) variant (Smith EH et al 2010. PubMed ID: 20434380), although it should be noted that the c.985A>G variant in the heterozygous state alone may lead to a false positive newborn screen suggestive of MCADD (Merritt and Chang. 2019. PubMed ID: 20301597). We have observed the c.127G>A variant internally in approximately a dozen individuals with suspected MCADD, many identified based on abnormal newborn screen results. In two individuals, we found no second ACADM variant whereas eight individuals were found to be heterozygous for both the c.127G>A variant and the common c.985A>G variant. The c.127G>A variant is listed in the ClinVar database with interpretations of pathogenic, uncertain significance, and likely benign (www.ncbi.nlm.nih.gov/clinvar/variation/92257). In summary, the clinical significance of this variant is currently uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.38

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D;D;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.2

.;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.83

P;P;P;B

Vest4

0.38

MVP

0.98

MPC

0.21

ClinPred

0.029

GERP RS

5.8

Varity_R

0.82

gMVP

0.37

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