rs786204424

Positions:

• chr1-75733624-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000016.6(ACADM):​c.387+1del variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L128L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ACADM NM_000016.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 U:1
• Conservation: PhyloP100: 1.93

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 1-75733624-TG-T is Pathogenic according to our data. Variant chr1-75733624-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 188719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.387+1del		frameshift_variant	5/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.387+1del		frameshift_variant	5/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251398 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458844 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725988

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2019	Variant summary: ACADM c.387+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The variant is located in a run of Gs, which results in the deletion of the last G located in a splicing region which several computational tools predict the variant to shift splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251398 control chromosomes (gnomAD). c.387+1delG has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Li_2019, Maier_2005, Sturm_2012, Waddell_2006, Bentler_2016). These data indicate that the variant is likely to be associated with disease. Sturm_2012 correlated residual MCAD activities with genotypes by measuring the octanoyl-CoA oxidation in lymphocytes and found the compound heterozygote patient to have a residual activity of 7%. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant once as pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	This sequence change affects a splice site in intron 5 of the ACADM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). This variant is present in population databases (rs754904305, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 15832312, 23028790). This variant is also known as IVS5+1delG. ClinVar contains an entry for this variant (Variation ID: 188719). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 11, 2018	The ACADM c.387+1delG variant (rs786204424), also known as IVS 5+1delG, is reported in the literature in a compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase deficiency (Bentler 2016, Maier 2005, Sturm 2012). This variant is reported in ClinVar (Variation ID: 188719), and is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 5, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Bentler K et al. 221 newborn-screened neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency: Findings from the Inborn Errors of Metabolism Collaborative. Mol Genet Metab. 2016 Sep;119(1-2):75-82. Maier EM et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005 May;25(5):443-52. Sturm M et al. Functional effects of different medium-chain acyl-CoA dehydrogenase genotypes and identification of asymptomatic variants. PLoS One. 2012;7(9):e45110. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 31, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 13, 2021	- -

not provided Pathogenic:2 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Oct 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 10, 2018	The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs786204424; hg19: chr1-76199309;