rs147559466

chr1-75732652-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8 B:2
• Conservation: PhyloP100: 7.34

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 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 GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	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	c.127G>A	p.Glu43Lys	missense_variant	3/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152068 Hom.: 0 Cov.: 33

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.: 2 AF XY: 0.00207 AC XY: 281 AN XY: 135862

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.: 5 Cov.: 30 AF XY: 0.00244 AC XY: 1774 AN XY: 726980

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.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74384

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.: 2

Bravo AF: 0.00165

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00224 AC: 272

EpiCase AF: 0.00294

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Uncertain:4 Benign:2

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	Invitae	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. -
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	MGZ Medical Genetics Center	Feb 07, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 17, 2021	- -
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:3 Uncertain:1

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	Eurofins Ntd Llc (ga)	Aug 06, 2012	- -
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 condition 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	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
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	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.50	T
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	T
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

Other links and lift over

dbSNP: rs147559466; hg19: chr1-76198337; COSMIC: COSV105927856; COSMIC: COSV105927856;