1-75724790-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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

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 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 51 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 as 370802
• 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 [Likely_pathogenic]. Clinvar id is 555765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.3G>C	p.Met1?	start_lost	Exon 1 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.3G>C	p.Met1?	start_lost	Exon 1 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACADM: PM2, PM3, PVS1:Moderate -

Nov 25, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is a known mechanism of disease -

Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2

Dec 29, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 555765). Disruption of the initiator codon has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 23028790, 30675864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ACADM mRNA. The next in-frame methionine is located at codon 87. -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.17	D
PROVEAN	Benign	-0.50	N;N;N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.021	B;B;B
Vest4		0.73
MutPred		0.94		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.73
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.94
gMVP		0.44

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: rs1553121887; hg19: chr1-76190475;