NM_000016.6:c.15C>A

Variant names:

• chr1-75724802-C-A
• rs1024056446
• NM_000016.6:c.15C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000016.6(ACADM):​c.15C>A​(p.Phe5Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADM NM_000016.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.91
• Publications: 0 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

ENSG00000293044 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09127885).

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.15C>A	p.Phe5Leu	missense	Exon 1 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.15C>A	p.Phe5Leu	missense	Exon 1 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.15C>A	p.Phe5Leu	missense	Exon 1 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.15C>A	p.Phe5Leu	missense	Exon 1 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.15C>A	p.Phe5Leu	missense	Exon 1 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.15C>A	p.Phe5Leu	missense	Exon 1 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1368108 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 676926

African (AFR) AF: 0.00 AC: 0 AN: 28494

American (AMR) AF: 0.00 AC: 0 AN: 33488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22520

East Asian (EAS) AF: 0.00 AC: 0 AN: 32822

South Asian (SAS) AF: 0.00 AC: 0 AN: 74534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5414

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063588

Other (OTH) AF: 0.00 AC: 0 AN: 55880

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	6.7
DANN	Benign	0.72
DEOGEN2	Benign	0.38	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.81	L
PhyloP100		-1.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.18	N
REVEL	Benign	0.21
Sift	Benign	0.71	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.40		Gain of helix (P = 0.0022)
MVP		0.53
MPC		0.22
ClinPred		0.068	T
GERP RS		-2.8
PromoterAI		-0.28	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.045
gMVP		0.16
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1024056446; hg19: chr1-76190487;