rs149678400

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 7P and 1B. PM1PM2PM5PP5BP4

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:6U:2

Conservation

PhyloP100: 3.41

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:

ACADM (HGNC:):

ACADM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000016.6

PM2

Very rare variant in population databases, with high coverage;

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 id is 1518981.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

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 id is 203538.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=3}.

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/exons	MANE	Protein	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.683C>A	p.Thr228Asn	missense_variant	8/12	ENST00000370841.9	NP_000007.1	P11310-1A0A0S2Z366

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9 linkuse as main transcript	c.683C>A	p.Thr228Asn	missense_variant	8/12	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

GnomAD3 exomes

AF:

0.000294

AC:

AN:

251280

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135834

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000171

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.0000957

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:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 20, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 01, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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; Invitae; 15171998 20434380). 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). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2024	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) -

ACADM-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2023

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

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;.;.

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

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