rs373852490

Variant names:

• chr1-75749438-G-A
• rs373852490
• NM_000016.6:c.728G>A
• ACADM p.Arg243Gln

Your query was ambiguous. Multiple possible variants found:

• chr1-75749438-G-A
• chr1-75749438-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP5

The NM_000016.6(ACADM):​c.728G>A​(p.Arg243Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R243R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.67
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000016.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 95 curated pathogenic missense variants (we use a threshold of 10). The gene has 29 curated benign missense variants. Gene score misZ: 0.54287 (below the threshold of 3.09). Trascript score misZ: 0.41658 (below the threshold of 3.09). GenCC associations: The gene is linked to medium chain acyl-CoA dehydrogenase deficiency.
• PP5: Variant 1-75749438-G-A is Pathogenic according to our data. Variant chr1-75749438-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 226088.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	NM_000016.6	MANE Select	c.728G>A	p.Arg243Gln	missense	Exon 9 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.827G>A	p.Arg276Gln	missense	Exon 10 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.740G>A	p.Arg247Gln	missense	Exon 9 of 12	NP_001120800.1	P11310-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACADM	ENST00000370841.9	TSL:1 MANE Select	c.728G>A	p.Arg243Gln	missense	Exon 9 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.827G>A	p.Arg276Gln	missense	Exon 10 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.740G>A	p.Arg247Gln	missense	Exon 9 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251290 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727162

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111918

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	2	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.62	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.90
gMVP		0.82
Mutation Taster		=32/68	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373852490;

hg19: chr1-76215123;