rs200754053

Positions:

• chr1-75740037-G-A
• chr1-75740037-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000016.6(ACADM):​c.526G>A​(p.Ala176Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A176S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.85

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 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-75740037-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226093.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=3, Pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 1-75740037-G-A is Pathogenic according to our data. Variant chr1-75740037-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495343.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.526G>A	p.Ala176Thr	missense_variant	7/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.526G>A	p.Ala176Thr	missense_variant	7/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251382 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135864

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460606 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726696

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 176 of the ACADM protein (p.Ala176Thr). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with ACADM-related conditions and/or medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18241067, 20036593, 20434380; Invitae). ClinVar contains an entry for this variant (Variation ID: 495343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function with a positive predictive value of 80%. This variant disrupts the p.Ala176 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2018	The ACADM c.526G>A; p.Ala176Thr variant, also known as Ala151Thr, has been described in the compound heterozygous state in individuals affected with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, presenting with elevated octanoylcarnitine (C8) levels (Arnold 2010, Nichols 2008, Smith 2010). It contains an entry in ClinVar (Variation ID: 495343), and is present on only 3 alleles in the Genome Aggregation Databases, indicating it is not a common polymorphism. The alanine at codon 176 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Based on available information, this variant is considered likely pathogenic. REFERENCES Arnold G et al. Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State. Mol Genet Metab. 2010 Mar;99(3):263-8. Nichols M et al. Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population. Am J Med Genet A. 2008 Mar 1;146A(5):610-9. Smith E et al. Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab. 2010 Jul;100(3):241-50. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 08, 2024	Described as a variant of uncertain significance and observed in the presence of a pathogenic variant in an individual with plasma and/or urine metabolites and biochemical studies similar to that of MCAD carriers (PMID: 20434380); Reported in individuals with a positive newborn screen for MCAD deficiency in whom a second variant was not described (PMID: 18241067, 20036593); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20036593, 27477829, 18241067, 20434380) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 12, 2017	Variant summary: The ACADM c.256G>A (p.Ala176Thr) variant involves the alteration of a highly conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The Ala176 codon is located just outside of the MCAD conserved domain active site. The variant is absent from control datasets of ExAC and gnomAD (120956 chrs and 277152chrs tested, respectively). The variant is reported in at least 2 pts in trans with known a pathogenic mutation, c.985A>G, resulting elevated octanoylcarnitine (C8) levels. On the other hand, in compound heterozygosity with c.199T>C patients C8 level was similar to carrier profiles. One reputable database/clinical laboratory cite the variant as Pathogenic. Taking together, the variant of interest was classified as VUS-Possibly Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.95
MutPred		0.95		.;.;Gain of phosphorylation at A209 (P = 0.0739);.;
MVP		1.0
MPC		0.68
ClinPred		0.97	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.91

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: rs200754053; hg19: chr1-76205722;