chr1-75761187-C-CCTAGAATGAGTTA

Variant names:

• chr1-75761187-C-CCTAGAATGAGTTA
• rs875989874
• NM_000016.6:c.1012_1013insTAGAATGAGTTAC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The ENST00000370841.9(ACADM):​c.1012_1013insTAGAATGAGTTAC​(p.Gln338LeufsTer3) variant causes a frameshift, stop gained 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 INS_BIG, 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. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADM ENST00000370841.9 frameshift, stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.26
• 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370841.9. 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.1012_1013insTAGAATGAGTTAC	p.Gln338LeufsTer3	frameshift stop_gained	Exon 11 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.1111_1112insTAGAATGAGTTAC	p.Gln371LeufsTer3	frameshift stop_gained	Exon 12 of 13	NP_001272972.1
	ACADM	NM_001127328.3		c.1024_1025insTAGAATGAGTTAC	p.Gln342LeufsTer3	frameshift stop_gained	Exon 11 of 12	NP_001120800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.1012_1013insTAGAATGAGTTAC	p.Gln338LeufsTer3	frameshift stop_gained	Exon 11 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.1111_1112insTAGAATGAGTTAC	p.Gln371LeufsTer3	frameshift stop_gained	Exon 12 of 13	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.1024_1025insTAGAATGAGTTAC	p.Gln342LeufsTer3	frameshift stop_gained	Exon 11 of 12	ENSP00000409612.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs875989874; hg19: chr1-76226872;