chr1-75728472-A-ATTAGGAT

Variant names:

• chr1-75728472-A-ATTAGGAT
• rs875989875
• NM_000016.6:c.107_113dupGATTTAG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000016.6(ACADM):​c.107_113dupGATTTAG​(p.Ser38ArgfsTer3) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACADM NM_000016.6 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0520
• 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-75728472-A-ATTAGGAT is Pathogenic according to our data. Variant chr1-75728472-A-ATTAGGAT is described in ClinVar as Pathogenic. ClinVar VariationId is 226104.Status of the report is criteria_provided_single_submitter, 1 stars.

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.107_113dupGATTTAG	p.Ser38ArgfsTer3	frameshift stop_gained	Exon 2 of 12	NP_000007.1
	ACADM	NM_001286043.2		c.107_113dupGATTTAG	p.Ser38ArgfsTer3	frameshift stop_gained	Exon 2 of 13	NP_001272972.1
	ACADM	NM_001127328.3		c.119_125dupGATTTAG	p.Ser42ArgfsTer3	frameshift stop_gained	Exon 2 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.107_113dupGATTTAG	p.Ser38ArgfsTer3	frameshift stop_gained	Exon 2 of 12	ENSP00000359878.5
	ACADM	ENST00000370834.9	TSL:1	c.107_113dupGATTTAG	p.Ser38ArgfsTer3	frameshift stop_gained	Exon 2 of 13	ENSP00000359871.5
	ACADM	ENST00000420607.6	TSL:1	c.119_125dupGATTTAG	p.Ser42ArgfsTer3	frameshift stop_gained	Exon 2 of 12	ENSP00000409612.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.052
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: rs875989875; hg19: chr1-76194157;