NM_000016.6:c.664_666delTTCinsCTG

Variant names:

• chr1-75745870-TTC-CTG
• NM_000016.6:c.664_666delTTCinsCTG
• ACADM p.Phe222Leu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP2 PP3

The NM_000016.6(ACADM):​c.664_666delTTCinsCTG​(p.Phe222Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.85
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• medium chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000016.6
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000016.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.664_666delTTCinsCTG	p.Phe222Leu	missense	N/A	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.763_765delTTCinsCTG	p.Phe255Leu	missense	N/A	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.676_678delTTCinsCTG	p.Phe226Leu	missense	N/A	NP_001120800.1	P11310-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.664_666delTTCinsCTG	p.Phe222Leu	missense	N/A	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.763_765delTTCinsCTG	p.Phe255Leu	missense	N/A	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.676_678delTTCinsCTG	p.Phe226Leu	missense	N/A	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.8

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-76211555;