1-75724788-A-G

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.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACADM NM_000016.6 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.25

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, no new inframe start found.
• PS1: Another start lost variant in NM_000016.6 (ACADM) was described as [Likely_pathogenic] in ClinVar as 555765
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-75724788-A-G is Pathogenic according to our data. Variant chr1-75724788-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.1A>G	p.Met1?	start_lost	1/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.1A>G	p.Met1?	start_lost	1/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1370182 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 678766

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370802). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 20, 2016	- -

not provided Other:1

not provided, no classification provided

in vitro

Seelig Lab, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Benign	19
Dann	Benign	0.78
DEOGEN2	Uncertain	0.43	T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.039	T
MutationTaster	Benign	1.0	D;D;D;N;N
PROVEAN	Benign	-0.47	N;N;N
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.0090	B;B;B
Vest4		0.65
MutPred		0.93		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.72
ClinPred		0.99	D
GERP RS		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.48

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: rs1057516778; hg19: chr1-76190473; COSMIC: COSV63719542; COSMIC: COSV63719542;