NM_000016.6:c.3G>C

Variant names:

• chr1-75724790-G-C
• rs1553121887
• NM_000016.6:c.3G>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_000016.6(ACADM):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACADM NM_000016.6 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.58
• 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 67 pathogenic variants. Next in-frame start position is after 87 codons. Genomic position: 75732895. Lost 0.205 part of the original CDS.
• PS1: Another start lost variant in NM_000016.6 (ACADM) was described as [Likely_pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-75724790-G-C is Pathogenic according to our data. Variant chr1-75724790-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 555765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.3G>C	p.Met1?	start_lost	Exon 1 of 12	NP_000007.1	A0A0S2Z366
	ACADM	NM_001286043.2		c.3G>C	p.Met1?	start_lost	Exon 1 of 13	NP_001272972.1	Q5T4U5
	ACADM	NM_001127328.3		c.3G>C	p.Met1?	start_lost	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.3G>C	p.Met1?	start_lost	Exon 1 of 12	ENSP00000359878.5	P11310-1
	ACADM	ENST00000370834.9	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 13	ENSP00000359871.5	Q5T4U5
	ACADM	ENST00000420607.6	TSL:1	c.3G>C	p.Met1?	start_lost	Exon 1 of 12	ENSP00000409612.2	P11310-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Medium-chain acyl-coenzyme A dehydrogenase deficiency (2)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.17	D
PhyloP100		3.6
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.021	B
Vest4		0.73
MutPred		0.94		Gain of sheet (P = 0.0827)
MVP		0.73
ClinPred		1.0	D
GERP RS		2.5
PromoterAI		-0.63	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.94
gMVP		0.44
Mutation Taster		=5/195	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: rs1553121887; hg19: chr1-76190475;