1-75745889-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1PM5PP2PP5BP4

The NM_000016.6(ACADM):c.683C>A(p.Thr228Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T228I) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 3.41

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

medium chain acyl-CoA dehydrogenase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Orphanet

ACADM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000016.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-75745889-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1518981.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.

PP5

Variant 1-75745889-C-A is Pathogenic according to our data. Variant chr1-75745889-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203538.

BP4

Computational evidence support a benign effect (MetaRNN=0.09839246). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6 link	c.683C>A	p.Thr228Asn	missense_variant	Exon 8 of 12	ENST00000370841.9	NP_000007.1	P11310-1A0A0S2Z366

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9 link	c.683C>A	p.Thr228Asn	missense_variant	Exon 8 of 12	1	NM_000016.6	ENSP00000359878.5		P11310-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.000132

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000294

AC:

AN:

251280

AF XY:

0.000265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000105

AC:

154

AN:

1460344

Hom.:

Cov.:

AF XY:

0.000100

AC XY:

AN XY:

726602

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00170

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000594

AC:

AN:

1110754

Other (OTH)

AF:

0.000199

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000171

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41524

American (AMR)

AF:

0.000720

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68004

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:6Uncertain:1

Mar 28, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 20, 2020

Illumina Laboratory Services, Illumina

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACADM c.683C>A (p.Thr228Asn) variant is a missense variant which has been reported in four studies in a compound heterozygous state in six individuals with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Hsu et al. 2008; Smith et al. 2010; Couce et al. 2013; Anderson et al. 2020). The p.Thr228Asn variant was also identified in another affected infant with a second variant, but the phase was not determined (McKinney et al. 2004). These individuals showed variable biochemical results including elevated acylglycines, serum medium chain acylcarnitines, C8-carnitine, C8/C10, and C8/C2 levels. However, some of biochemical parameters were within normal range in these individuals and it is suggested that this variant confers an attenuated effect (Smith et al. 2010; Couce et al. 2013; Anderson et al. 2020). The p.Thr228Asn variant is reported at a frequency of 0.001580 in the Latino/Admixed American population of the Genome Aggregation Database in a region of good sequence coverage. Based on collective evidence, the p.Thr228Asn variant is classified as likely pathogenic for medium-chain acyl-CoA dehydrogenase deficiency. -

Sep 01, 2024

Department of Genetics of Metabolic Diseases, Institute of Medical & Molecular Genetics, Hospital Universitario Hospital La Paz

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant NM_000016.5:c.683C>A p.(Thr228Asn) in ACADM is present at low frequency in gnomAD (0.02689%). Functional studies in fibroblasts confirm this variant reduces significatively MCAD´s activity (PMID: 23028790). This variant has been observed in compound heterozygous newborns with levels of C8 at NBS consistent with MCADD (PMID: 23842438, 35629059, 18450854, Hidalgo Mayoral I et al., in press) -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 228 of the ACADM protein (p.Thr228Asn). This variant is present in population databases (rs149678400, gnomAD 0.2%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 23842438; 15171998 20434380, internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203538). 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 not expected to disrupt ACADM protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Feb 20, 2015

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 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: ACADM c.683C>A (p.Thr228Asn) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251280 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00029 vs 0.0054), allowing no conclusion about variant significance. c.683C>A has been reported in the literature in settings of newborn screening (NBS) in compound heterozygosity with other variants in this gene including multiple individuals with a pathogenic second variant in trans (example, McKinney_2004, Smith_2010, Couce_2013, Navarrete_2019, Anderson_2020, Alcaide_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20434380, 15171998, 23842438, 31836396, 30626930, 35629059). ClinVar contains an entry for this variant (Variation ID: 203538). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Uncertain:2

Jan 30, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(T203N); This variant is associated with the following publications: (PMID: 20434380, 26764160, 32778825, 23842438, 35629059, 31836396, 15171998, 18450854, 35281663, 23798014) -

Feb 17, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ACADM-related disorder

Pathogenic:1

Jun 30, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACADM c.683C>A variant is predicted to result in the amino acid substitution p.Thr228Asn. This variant has been reported in the compound heterozygous state in over twelve individuals with biochemical medium chain acyl CoA dehydrogenase deficiency (Table 4 in McKinney et al 2004. PubMed ID: 15171998; Table 2 in Smith EH et al 2010. PubMed ID: 20434380; Couce ML et al 2013. PubMed ID: 23842438; Navarrete R et al 2019. PubMed ID: 30626930; Alcaide P. et al. 2022. PubMed ID: 35629059). In some patients this variant is predicted to mildly raise c8-carnitine levels and therefore many patients are only mildly affected or may be clinically asymptomatic (Anderson DR et al 2019. PubMed ID: 31836396; Alcaide P. et al. 2022. PubMed ID: 35629059). Lymphocytes from a patient with the c.683C>A variant in combination with a null variant exhibited 31% enzyme activity (Alcaide P. et al. 2022. PubMed ID: 35629059). This variant is reported in 0.16% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-76211574-C-A). In summary, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;D;D;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.46

MetaRNN

Benign

0.098

T;T;T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.4

.;M;.;.

PhyloP100

3.4

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Uncertain

0.60

Sift

Benign

0.030

D;D;D;D

Sift4G

Uncertain

0.041

D;D;D;D

Polyphen

0.35

B;B;P;P

Vest4

0.48

MVP

0.95

MPC

0.45

ClinPred

0.13

GERP RS

4.9

Varity_R

0.73

gMVP

0.69

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over