1-75724781-AGCCAACATGGCA-AACCCCGAAGG

Variant names:

• chr1-75724782-GCCAACATGGCA-ACCCCGAAGG
• rs875989865
• NM_000016.6:c.-6_6delGCCAACATGGCAinsACCCCGAAGG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_000016.6(ACADM):​c.-6_6delGCCAACATGGCAinsACCCCGAAGG​(p.Met1fs) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADM NM_000016.6 frameshift, start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.58
• 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, ClinGen, Orphanet

ENSG00000293044 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 309 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000016.6 (ACADM) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.-6_6delGCCAACATGGCAinsACCCCGAAGG	p.Met1fs	frameshift start_lost	Exon 1 of 12	NP_000007.1
	ACADM	NM_000016.6	MANE Select	c.-6_6delGCCAACATGGCAinsACCCCGAAGG		5_prime_UTR	Exon 1 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.-6_6delGCCAACATGGCAinsACCCCGAAGG	p.Met1fs	frameshift start_lost	Exon 1 of 13	NP_001272972.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.-6_6delGCCAACATGGCAinsACCCCGAAGG	p.Met1fs	frameshift start_lost	Exon 1 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.-6_6delGCCAACATGGCAinsACCCCGAAGG	p.Met1fs	frameshift start_lost	Exon 1 of 13	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.-6_6delGCCAACATGGCAinsACCCCGAAGG	p.Met1fs	frameshift start_lost	Exon 1 of 12	ENSP00000409612.2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6

Splicing

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

Other links and lift over

dbSNP: rs875989865; hg19: chr1-76190467;