chr1-75740037-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM5PP2PP3_ModeratePP5

The NM_000016.6(ACADM):c.526G>T(p.Ala176Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,612,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A176T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 9.85

Publications

9 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: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000016.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-75740037-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 495343.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

PP5

Variant 1-75740037-G-T is Pathogenic according to our data. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093. Variant chr1-75740037-G-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 226093.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6 link	c.526G>T	p.Ala176Ser	missense_variant	Exon 7 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.526G>T	p.Ala176Ser	missense_variant	Exon 7 of 12	1	NM_000016.6	ENSP00000359878.5		P11310-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000544

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000171

AC:

AN:

251382

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000396

AC:

579

AN:

1460606

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

264

AN XY:

726696

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33442

American (AMR)

AF:

0.000134

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000493

AC:

548

AN:

1111094

Other (OTH)

AF:

0.000331

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000276

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68018

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000348

Hom.:

Bravo

AF:

0.000306

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency

Pathogenic:3Uncertain:3

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 176 of the ACADM protein (p.Ala176Ser). This variant is present in population databases (rs200754053, gnomAD 0.03%). This missense change has been observed in individual(s) with MCAD (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: 226093). 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:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 25, 2018

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1

May 21, 2025

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.526G>T (p.Ala176Ser) results in a conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00017 in 251382 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00017 vs 0.0054), allowing no conclusion about variant significance. c.526G>T has been observed in individual(s) affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (internal data). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 226093). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

ACADM-related disorder

Uncertain:1

Apr 01, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ACADM c.526G>T variant is predicted to result in the amino acid substitution p.Ala176Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.035% of alleles in individuals of European (non-Finnish) descent in gnomAD. An alternate nucleotide substitution affecting the same amino acid (p.Ala176Thr) has been reported in the heterozygous state in an individual with medium chain acyl-CoA dehydrogenase deficiency (reported as p.Ala151Thr in Table 2, Nichols et al. 2008. PubMed ID: 18241067). Although we suspect that the c.526G>T (p.Ala176Ser) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;D;D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.99

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.8

.;H;.;.

PhyloP100

9.8

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0080

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

0.99

D;P;D;P

Vest4

0.85

MVP

1.0

MPC

0.54

ClinPred

0.80

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.86

Mutation Taster

=168/132

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