1-75724782-GCCAACATGGCA-ACCCCGAGTG

Position:

• chr1-75724782-GCCAACATGGCA-ACCCCGAGTG

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000016.6(ACADM):​c.-6_6delGCCAACATGGCAinsACCCCGAGTG​(p.Met1fs) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADM NM_000016.6 frameshift, start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.58

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 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 229 pathogenic variants in the truncated region.
• PS1: Another start lost variant in NM_000016.6 (ACADM) was described as [Likely_pathogenic] in ClinVar as 555765
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-75724782-GCCAACATGGCA-ACCCCGAGTG is Pathogenic according to our data. Variant chr1-75724782-GCCAACATGGCA-ACCCCGAGTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 966945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACADM	NM_000016.6	c.-6_6delGCCAACATGGCAinsACCCCGAGTG	p.Met1fs	frameshift_variant, start_lost	1/12	ENST00000370841.9	NP_000007.1
ACADM	NM_000016.6	c.-6_6delGCCAACATGGCAinsACCCCGAGTG		5_prime_UTR_variant	1/12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.-6_6delGCCAACATGGCAinsACCCCGAGTG	p.Met1fs	frameshift_variant, start_lost	1/12	1	NM_000016.6	ENSP00000359878.5
ACADM	ENST00000370841	c.-6_6delGCCAACATGGCAinsACCCCGAGTG		5_prime_UTR_variant	1/12	1	NM_000016.6	ENSP00000359878.5

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

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2022	This sequence change affects the initiator methionine of the ACADM mRNA. The next in-frame methionine is located at codon 87. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with medium chain acyl-CoA dehydrogenase deficiency (PMID: 23028790, 30675864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 966945). This variant disrupts a region of the ACADM protein in which other variant(s) (p.Arg29Leu) have been determined to be pathogenic (PMID: 20434380; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 12, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs875989865; hg19: chr1-76190467;