1-75732659-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000016.6(ACADM):​c.134A>G​(p.Gln45Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,576 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q45H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 8.61
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 16 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
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-75732660-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2010808.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.935
PP5
Variant 1-75732659-A-G is Pathogenic according to our data. Variant chr1-75732659-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281077.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.134A>G p.Gln45Arg 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.134A>G p.Gln45Arg missense_variant Exon 3 of 12 1 NM_000016.6 ENSP00000359878.5 P11310-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251266
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135864
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461576
Hom.:
0
Cov.:
30
AF XY:
0.00000688
AC XY:
5
AN XY:
727102
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000457
Hom.:
0
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:4Uncertain:1
Mar 11, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the ACADM protein (p.Gln45Arg). This variant is present in population databases (rs757434857, gnomAD 0.006%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 18241067, 20434380, 22796001; Invitae). 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: 281077). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADM protein function. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). For these reasons, this variant has been classified as Pathogenic. -

Nov 30, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 27, 2017
Counsyl
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Mar 17, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: ACADM c.134A>G (p.Gln45Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) 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 1.6e-05 in 251266 control chromosomes (gnomAD). c.134A>G has been reported in the literature in the compound heterozygous state in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Nichols_2008, Purevsuren_2009, Rucklova_2021). These data indicate that the variant may be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function found that the variant resulted in reduced protein expression, which was prone to misfolding and/or aggregation, and that the variant had 11% of normal activity (Hara_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic, likely pathogenic, and VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Jun 23, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Jul 06, 2017
Eurofins Ntd Llc (ga)
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

ACADM-related disorder Pathogenic:1
Jul 30, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The ACADM c.134A>G variant is predicted to result in the amino acid substitution p.Gln45Arg. This variant has been reported with other ACADM variants in multiple individuals with biochemical features consistent with medium-chain acyl-CoA dehydrogenase deficiency (see for example, Nichols et al. 2008. PubMed ID: 18241067; Purevsuren et al. 2008. PubMed ID: 19064330; Table S2, Rücklová et al. 2021. PubMed ID: 34578803). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study suggests this variant affects protein expression and MCAD enzyme activity (Hara et al. 2015. PubMed ID: 26947917). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;D;D;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.93
D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.8
.;H;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-3.3
D;D;D;D
REVEL
Pathogenic
0.96
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.0080
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.79
MutPred
0.76
.;Gain of MoRF binding (P = 0.0513);Gain of MoRF binding (P = 0.0513);.;
MVP
0.99
MPC
0.77
ClinPred
0.97
D
GERP RS
5.8
Varity_R
0.92
gMVP
0.85

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: rs757434857; hg19: chr1-76198344; API