rs147559466

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

5
11
3

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]

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 8 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 rank MANE Protein UniProt
ACADMNM_000016.6 linkc.127G>A p.Glu43Lys missense_variant Exon 3 of 12 ENST00000370841.9 NP_000007.1 P11310-1A0A0S2Z366

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACADMENST00000370841.9 linkc.127G>A p.Glu43Lys missense_variant Exon 3 of 12 1 NM_000016.6 ENSP00000359878.5 P11310-1

Frequencies

GnomAD3 genomes
AF:
0.00208
AC:
317
AN:
152068
Hom.:
0
Cov.:
33
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.:
2
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.:
5
Cov.:
30
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.:
0
Cov.:
33
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.:
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:3Uncertain:9Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Uncertain:5Benign:2
Jul 26, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 17, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 07, 2022
MGZ Medical Genetics Center
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 28, 2019
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Oct 28, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

not provided Pathogenic:3Uncertain:1
Mar 30, 2015
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACADM: PM2, PM3, BS2 -

Aug 23, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 06, 2012
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:1
Sep 09, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ACADM c.127G>A (p.Glu43Lys) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (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. c.127G>A has been reported in several subjects during newborn screening programs in the compound heterozygous state with another pathogenic variant c.985A>G (e.g. Smith_2010, Sturm_2012, Catarzi_2013, Navarrete_ 2019, Jager_ 2019, Anderson_ 2019, Alcaide_2022). However, most were biochemically indistinguishable from MCAD carriers, suggesting this variant is likely innocuous. In addition, an asymptomatic father of a homozygous MCAD deficient child 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). A functional study (Koster_2014) showed the variant was comparable to WT in specificity to substrates C8-CoA and C12-CoA, and had ~60% of WT level of specificity to substrate C10-CoA, and the residual activity of the variant was improved by co-overexpression with molecular chaperones, with the variant showing >100% of WT activity. The following publications have been ascertained in the context of this evaluation (PMID: 23028790, 20434380, 15171998, 24966162, 27843123, 24294134, 31836396, 30626930, 31012112, 35629059). ClinVar contains an entry for this variant (Variation ID: 92257). Based on the evidence outlined above, the variant was classified as uncertain significance. -

See cases Uncertain:1
Oct 21, 2020
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PM3, PP3, BS1 -

ACADM-related disorder Uncertain:1
Aug 31, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
MutationAssessor
Uncertain
2.2
.;M;.;.
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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