chr1-75734864-T-G

Position:

• chr1-75734864-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The ENST00000370841.9(ACADM):​c.461T>G​(p.Leu154Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L154L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ACADM ENST00000370841.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.83

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000370841.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• PP5: Variant 1-75734864-T-G is Pathogenic according to our data. Variant chr1-75734864-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 557423.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6	c.461T>G	p.Leu154Trp	missense_variant	6/12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.461T>G	p.Leu154Trp	missense_variant	6/12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 21, 2023	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: 557423). This missense change has been observed in individual(s) with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 21239873, 33841490). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 154 of the ACADM protein (p.Leu154Trp). This variant is not present in population databases (gnomAD no frequency). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 24, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 03, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Benign	0.39	T;D;T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.79	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.93	.;L;.;.
MutationTaster	Benign	0.92	D;D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.022	D;D;D;D
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.57
MutPred		0.37		.;.;Gain of catalytic residue at L187 (P = 0.005);.;
MVP		0.97
MPC		0.93
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.52
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1553123263; hg19: chr1-76200549;