rs121434275

Positions:

• chr1-75761300-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000016.6(ACADM):​c.1124T>C​(p.Ile375Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,228 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. I375M) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.36

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 10 ACMG points.

• PM1: In a helix (size 25) in uniprot entity ACADM_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-75761300-T-C is Pathogenic according to our data. Variant chr1-75761300-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3589.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.1124T>C	p.Ile375Thr	missense_variant	11/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.1124T>C	p.Ile375Thr	missense_variant	11/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 05, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 375 of the ACADM protein (p.Ile375Thr). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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 expected to disrupt ACADM protein function. ClinVar contains an entry for this variant (Variation ID: 3589). This missense change has been observed in individual(s) with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 1684086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121434275, gnomAD 0.1%). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1991	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.95	P;P;B;D
Vest4		0.94
MutPred		0.91		.;.;Loss of stability (P = 0.0209);.;
MVP		0.98
MPC		0.84
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
gMVP		0.94

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

Other links and lift over

dbSNP: rs121434275; hg19: chr1-76226985;