rs370523609

chr1-75745788-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_000016.6(ACADM):c.600-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,544,834 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 1.24

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 Likely_pathogenic. Variant got 7 ACMG points.

• PP5: Variant 1-75745788-G-A is Pathogenic according to our data. Variant chr1-75745788-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 226084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.600-18G>A		intron_variant		ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.600-18G>A		intron_variant		1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152108 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000255 AC: 64 AN: 251270 Hom.: 0 AF XY: 0.000294 AC XY: 40 AN XY: 135828

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000207 AC: 288 AN: 1392608 Hom.: 1 Cov.: 23 AF XY: 0.000207 AC XY: 144 AN XY: 697316

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000896

Gnomad4 ASJ exome AF: 0.00257

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152226 Hom.: 1 Cov.: 33 AF XY: 0.000564 AC XY: 42 AN XY: 74408

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.00105

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:9

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 18, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000016.4(ACADM):c.600-18G>A is classified as likely pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency and is associated with a variable presentation, ranging from clinically asymptomatic to mild. Sources cited for classification include the following: PMID 31012112, 25255367, 20434380, 27477829, 26223887, 27308838 and 30626930. Classification of NM_000016.4(ACADM):c.600-18G>A is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 31, 2020	The c.612-18G>A (also known as c.600-18G>A, NM_000016.4) variant in ACADM has been reported in at least 8 individuals affected with mild medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the compound heterozygous state (variant in trans in at least 3 of these cases was the common c.985A > G (p.K329E); Smith 2010, Grunert 2015, Narravula 2017) . Additionally, the c.612-18G>A variant segregated with disease in 1 affected family member (Grunert 2015). This variant has also been reported in ClinVar (variation ID 226084). It has been identified in 0.2% (24/10364) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vivo and in vitro functional assays provide evidence that this variant lead to partial missplicing of the ACADM pre-mRNA and thereby affected protein function (Grunert 2015). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. ACMG/AMP Criteria applied: PM3_strong, PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 14, 2023	Variant summary: Variant summary: ACADM c.600-18G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes or weakens a cryptic 5' donor site, while two predict the variant creates a novel, cryptic 3' acceptor site, by introducing a novel AG upstream of the authentic 3' splice site AG. At least one publication reports experimental evidence demonstrating that this variant creates a cryptic 3' acceptor site that competes with the original 3' splice site, thus resulting in a partial splicing defect (Grunert_2015). The variant allele was found at a frequency of 0.00025 in 251270 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00025 vs 0.0054), allowing no conclusion about variant significance. The variant, c.600-18G>A has been reported in the literature in multiple compound heterozygous individuals (who also carried a second pathogenic variant), detected during newborn screening in mostly clinically asymptomatic individuals as a biochemical phenotype (e.g. Touw_2012, Grunert_2015, Jager_2019), or in some cases in individuals with a reportedly milder form of Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Smith_2010). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant might represent a hypomorphic allele with variable penetrance, therefore it was classified as pathogenic for a milder disease phenotype. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change falls in intron 7 of the ACADM gene. It does not directly change the encoded amino acid sequence of the ACADM protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370523609, gnomAD 0.2%). This variant has been observed in individual(s) with mild medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency on biochemical testing (PMID: 20434380, 26223887, 27308838, 27477829). 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: 226084). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 26223887). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 28, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 30, 2022	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2022	Published functional studies suggest this variant leads to partial mis-splicing of the ACADM pre-mRNA (Grunert et al., 2015); This variant is associated with the following publications: (PMID: 22630369, 20434380, 27308838, 27477829, 26223887, 31012112, 30626930, 34426522, 32778825) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 03, 2019	The gain of a new splice site is predicted. Nucleotide conservation is uninformative. Occurs in multiple cases with a lone recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 31, 2015	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.600-18G>A intronic alteration consists of a G to A substitution 18 nucleotides before coding exon 8 in the ACADM gene. This variant has been identified in apparently unaffected homozygous individuals in our laboratory (Ambry internal data). This alteration has been reported in the compound heterozygote states in individuals with medium chain acyl CoA dehydrogenase deficiency (Grünert, 2015; Navarrete, 2019; Smith, 2010; Touw, 2012). This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in an incomplete splice defect (Grünert, 2015). RNA studies have demonstrated that this alteration results in an incomplete splice defect (Grünert, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	9.6
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs370523609; hg19: chr1-76211473;