1-75761221-C-G

Variant names:

• chr1-75761221-C-G
• NM_000016.6:c.1045C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_000016.6(ACADM):​c.1045C>G​(p.Arg349Gly) variant causes a missense change involving the alteration of a non-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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R349L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.50

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75761222-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1433388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754
• PP5: Variant 1-75761221-C-G is Pathogenic according to our data. Variant chr1-75761221-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1068571.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.1045C>G	p.Arg349Gly	missense_variant	Exon 11 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.1045C>G	p.Arg349Gly	missense_variant	Exon 11 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 expected to disrupt ACADM protein function. This variant has been observed in an individual with medium chain acyl-CoA dehydrogenase deficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 349 of the ACADM protein (p.Arg349Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D;D;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.7	.;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.4	D;D;D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.93	P;P;P;P
Vest4		0.66
MutPred		0.52		.;.;Loss of stability (P = 0.0075);.;
MVP		0.94
MPC		0.36
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-76226906;