rs1061337

chr1-75761337-A-Gchr1-75761337-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000016.6(ACADM):c.1161A>G(p.Val387=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,518 control chromosomes in the GnomAD database, including 62,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V387V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (4582 hom., cov: 32)
  • Exomes 𝑓: 0.27 (57622 hom.)
• Consequence: ACADM NM_000016.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.28

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-75761337-A-G is Benign according to our data. Variant chr1-75761337-A-G is described in ClinVar as [Benign]. Clinvar id is 92254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75761337-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.1161A>G	p.Val387=	synonymous_variant	11/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.1161A>G	p.Val387=	synonymous_variant	11/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35826 AN: 152028 Hom.: 4582 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.254

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.258

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.242

GnomAD3 exomes AF: 0.234 AC: 58625 AN: 250748 Hom.: 7439 AF XY: 0.236 AC XY: 31940 AN XY: 135512

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.209

Gnomad EAS exome AF: 0.0254

Gnomad SAS exome AF: 0.188

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.295

Gnomad OTH exome AF: 0.265

GnomAD4 exome AF: 0.274 AC: 400907 AN: 1461372 Hom.: 57622 Cov.: 34 AF XY: 0.272 AC XY: 197437 AN XY: 727024

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.0299

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.256

Gnomad4 NFE exome AF: 0.300

Gnomad4 OTH exome AF: 0.258

GnomAD4 genome AF: 0.236 AC: 35835 AN: 152146 Hom.: 4582 Cov.: 32 AF XY: 0.232 AC XY: 17278 AN XY: 74378

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.254

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.0336

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.301

Gnomad4 OTH AF: 0.241

Alfa AF: 0.278 Hom.: 9114

Bravo AF: 0.230

Asia WGS AF: 0.163 AC: 568 AN: 3478

EpiCase AF: 0.297

EpiControl AF: 0.297

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 17, 2021	The p.Val391Val variant in ACADM is not expected to have clinical significance because it has been identified in 29% (37908/128544) of European chromosomes, including 5448 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). -

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 23810226) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	6.3
Dann	Benign	0.67

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: rs1061337; hg19: chr1-76227022; COSMIC: COSV63720150; COSMIC: COSV63720150;