GeneBe

rs768884003

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000016.6(ACADM):​c.757G>A​(p.Glu253Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,908 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

11
6
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.76
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 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, 8 uncertain in NM_000016.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.915
PP5
Variant 1-75749467-G-A is Pathogenic according to our data. Variant chr1-75749467-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226054.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACADMNM_000016.6 linkc.757G>A p.Glu253Lys missense_variant Exon 9 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.757G>A p.Glu253Lys missense_variant Exon 9 of 12 1 NM_000016.6 ENSP00000359878.5 P11310-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152132
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251378
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461776
Hom.:
0
Cov.:
31
AF XY:
0.00000550
AC XY:
4
AN XY:
727192
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152132
Hom.:
1
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:6
Dec 12, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
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 253 of the ACADM protein (p.Glu253Lys). This variant is present in population databases (rs768884003, gnomAD 0.006%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 20434380; internal data). ClinVar contains an entry for this variant (Variation ID: 226054). 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

- -

Oct 04, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 26, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 15, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 19, 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.757G>A (p.Glu253Lys) results in a 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 8e-06 in 251378 control chromosomes (gnomAD). c.757G>A has been reported in the literature as a compound heterozygous genotype in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Smith_2010, Gong_2021) and in one affected individual in the homozygous state (Tajima_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence showing that cells from a patient homozygous for the variant of interest had normal enzymatic activity in vitro (Tajima_2016), however the authors speculate that the assay conditions do not faithfully replicate what occurs in vivo, allowing no convincing conclusion about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 33841490, 20434380, 27856190). ClinVar contains an entry for this variant (Variation ID: 226054). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D;D;D;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Pathogenic
0.92
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.3
.;M;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.8
D;D;D;D
REVEL
Pathogenic
0.92
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.046
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.95
MutPred
0.65
.;.;Gain of methylation at E286 (P = 0.0022);.;
MVP
0.99
MPC
0.29
ClinPred
0.96
D
GERP RS
5.9
Varity_R
0.91
gMVP
0.83

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: rs768884003; hg19: chr1-76215152; COSMIC: COSV57714382; COSMIC: COSV57714382; API