rs751829413

chr1-75745815-A-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000016.6(ACADM):c.609A>C(p.Leu203Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,920 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.232

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 1-75745815-A-C is Pathogenic according to our data. Variant chr1-75745815-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.609A>C	p.Leu203Phe	missense_variant	8/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.609A>C	p.Leu203Phe	missense_variant	8/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251376 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135858

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: 0.00000274 AC: 4 AN: 1460798 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152122 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

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: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 203 of the ACADM protein (p.Leu203Phe). This variant is present in population databases (rs751829413, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 16972171, 31012112; 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: 226065). 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	Baylor Genetics	Sep 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.17	N
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.79	P;P;P;P
Vest4		0.82
MutPred		0.85		.;.;Gain of sheet (P = 0.1208);.;
MVP		0.85
MPC		0.21
ClinPred		0.80	D
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

Other links and lift over

dbSNP: rs751829413; hg19: chr1-76211500;