rs768884003

Positions:

chr1-75749467-G-A

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

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]

ACADM links:

ACADM (HGNC:):

ACADM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 4 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/exons	MANE	Protein	UniProt
ACADM	NM_000016.6 linkuse as main transcript	c.757G>A	p.Glu253Lys	missense_variant	9/12	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.757G>A	p.Glu253Lys	missense_variant	9/12	1	NM_000016.6	ENSP00000359878.5		P11310-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152132

Hom.:

Cov.:

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:

AN:

251378

Hom.:

AF XY:

0.00000736

AC XY:

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:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

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:

AN:

152132

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

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:

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

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 226054). 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 04, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 15, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

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

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

.;M;.;.

PrimateAI

Uncertain

0.76

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

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.

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