rs121434277

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1_Very_StrongPM1PM2PP3_ModeratePP5_Very_Strong

The NM_000016.6(ACADM):c.447G>A(p.Met149Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,532 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 nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ACADM
NM_000016.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PS1

Transcript NM_000016.6 (ACADM) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 226059

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000016.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 1-75734850-G-A is Pathogenic according to our data. Variant chr1-75734850-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.447G>A	p.Met149Ile	missense_variant	6/12	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.447G>A	p.Met149Ile	missense_variant	6/12	1	NM_000016.6	ENSP00000359878.5		P11310-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727000

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.00000378

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:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 12, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2022	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 3591). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 1684086, 9158144). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 149 of the ACADM protein (p.Met149Ile). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2024	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 13, 2014

- -

ACADM-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 31, 2023

The ACADM c.447G>A variant is predicted to result in the amino acid substitution p.Met149Ile. This variant has been reported, along with the common c.985A>G (p.Lys329Glu) variant, in patients with medium chain acyl-CoA dehydrogenase deficiency (MCADD), one of whom presented with clinical symptoms before newborn screening was completed (Yokota et al 1991. PubMed ID: 1684086; Andresen et al. 1997. PubMed ID: 9158144, described as M124I based on legacy nomenclature; Anderson et al. 2020. PubMed ID: 31836396). The c.447G>A and c.985A>G variants were reported to segregate with disease in siblings in two unrelated families. All four reported siblings were clinically asymptomatic (Andresen et al. 1997. PubMed ID: 9158144). In an expression study using E. coli cells, the p.Met149Ile substitution was reported to greatly reduce enzyme activity relative to control (Andresen et al. 1997. PubMed ID: 9158144). We have also observed this variant internally, in the compound heterozygous state with the c.985A>G variant, in more than one patient with positive newborn screen results for MCADD. Taken together, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D;D;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.3

.;L;.;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.086

T;D;D;D

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.16

B;B;B;B

Vest4

0.68

MutPred

0.68

.;.;Gain of catalytic residue at L187 (P = 0.0219);.;

MVP

0.94

MPC

0.21

ClinPred

0.87

GERP RS

5.6

Varity_R

0.52

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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