NM_000016.6:c.127G>A

Variant names:

• chr1-75732652-G-A
• rs147559466
• NM_000016.6:c.127G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 7P and 5B. PS3 PM1 PP2 BP4_Strong BS2_Supporting

The NM_000016.6(ACADM):​c.127G>A​(p.Glu43Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,613,494 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005423839: Functional studies in fibroblasts confirm this variant reduces MCAD´s activity up to 15-40%. PMID:23028790".

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:10 B:2
• Conservation: PhyloP100: 7.34
• Publications: 18 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005423839: Functional studies in fibroblasts confirm this variant reduces MCAD´s activity up to 15-40%. PMID:23028790
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000016.6
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.010578901).
• BS2: High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.127G>A	p.Glu43Lys	missense	Exon 3 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.127G>A	p.Glu43Lys	missense	Exon 3 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.139G>A	p.Glu47Lys	missense	Exon 3 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.127G>A	p.Glu43Lys	missense	Exon 3 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.127G>A	p.Glu43Lys	missense	Exon 3 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.139G>A	p.Glu47Lys	missense	Exon 3 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 317 AN: 152068 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00293

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00206 AC: 517 AN: 251212 AF XY: 0.00207

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00294

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00245 AC: 3580 AN: 1461308 Hom.: 5 Cov.: 30 AF XY: 0.00244 AC XY: 1774 AN XY: 726980

African (AFR) AF: 0.000239 AC: 8 AN: 33466

American (AMR) AF: 0.00101 AC: 45 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000754 AC: 65 AN: 86232

European-Finnish (FIN) AF: 0.00255 AC: 136 AN: 53416

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00276 AC: 3071 AN: 1111564

Other (OTH) AF: 0.00220 AC: 133 AN: 60370

GnomAD4 genome AF: 0.00207 AC: 315 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74384

African (AFR) AF: 0.000434 AC: 18 AN: 41522

American (AMR) AF: 0.000785 AC: 12 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00293 AC: 31 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68004

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00245 Hom.: 4

Bravo AF: 0.00165

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00224 AC: 272

EpiCase AF: 0.00294

EpiControl AF: 0.00350

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	6	2	Medium-chain acyl-coenzyme A dehydrogenase deficiency (9)
4	1	-	not provided (5)
-	1	-	ACADM-related disorder (1)
-	1	-	not specified (1)
-	1	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.011	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.015	D
Polyphen		0.83	P
Vest4		0.38
MVP		0.98
MPC		0.21
ClinPred		0.029	T
GERP RS		5.8
Varity_R		0.82
gMVP		0.37
Mutation Taster		=210/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs147559466; hg19: chr1-76198337; COSMIC: COSV105927856; COSMIC: COSV105927856;