1-75732751-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000016.6(ACADM):c.216+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,609,978 control chromosomes in the GnomAD database, including 80,049 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7012 hom., cov: 33)
  • Exomes 𝑓: 0.31 (73037 hom.)
• Consequence: ACADM NM_000016.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00800

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 1-75732751-T-C is Benign according to our data. Variant chr1-75732751-T-C is described in ClinVar as [Benign]. Clinvar id is 92259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.216+10T>C		intron_variant		ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.216+10T>C		intron_variant		1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45515 AN: 152008 Hom.: 7008 Cov.: 33

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.285

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.276 AC: 69280 AN: 251044 Hom.: 10214 AF XY: 0.273 AC XY: 37074 AN XY: 135832

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.0260

Gnomad SAS exome AF: 0.201

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.310 AC: 452413 AN: 1457852 Hom.: 73037 Cov.: 30 AF XY: 0.306 AC XY: 222146 AN XY: 725560

Gnomad4 AFR exome AF: 0.295

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.197

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.334

Gnomad4 OTH exome AF: 0.294

GnomAD4 genome AF: 0.299 AC: 45550 AN: 152126 Hom.: 7012 Cov.: 33 AF XY: 0.294 AC XY: 21896 AN XY: 74358

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.0347

Gnomad4 SAS AF: 0.200

Gnomad4 FIN AF: 0.285

Gnomad4 NFE AF: 0.334

Gnomad4 OTH AF: 0.295

Alfa AF: 0.306 Hom.: 2383

Bravo AF: 0.302

Asia WGS AF: 0.182 AC: 633 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	15
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2275378; hg19: chr1-76198436;