chr1-75733592-A-C

Variant names:

• chr1-75733592-A-C
• rs74090726
• NM_000016.6:c.351A>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.351A>C​(p.Thr117Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 1,613,988 control chromosomes in the GnomAD database, including 1,141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (276 hom., cov: 33)
  • Exomes 𝑓: 0.029 (865 hom.)
• Consequence: ACADM NM_000016.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.388

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=-0.56).
• BP6: Variant 1-75733592-A-C is Benign according to our data. Variant chr1-75733592-A-C is described in ClinVar as [Benign]. Clinvar id is 92263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-75733592-A-C is described in Lovd as [Likely_benign]. Variant chr1-75733592-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADM	NM_000016.6	c.351A>C	p.Thr117Thr	synonymous_variant	Exon 5 of 12	ENST00000370841.9	NP_000007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADM	ENST00000370841.9	c.351A>C	p.Thr117Thr	synonymous_variant	Exon 5 of 12	1	NM_000016.6	ENSP00000359878.5

Frequencies

GnomAD3 genomes AF: 0.0489 AC: 7442 AN: 152150 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0353

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0398

GnomAD3 exomes AF: 0.0269 AC: 6760 AN: 251442 Hom.: 153 AF XY: 0.0250 AC XY: 3403 AN XY: 135896

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00787

Gnomad FIN exome AF: 0.0203

Gnomad NFE exome AF: 0.0284

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0293 AC: 42870 AN: 1461720 Hom.: 865 Cov.: 31 AF XY: 0.0284 AC XY: 20637 AN XY: 727168

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0256

Gnomad4 ASJ exome AF: 0.00436

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00808

Gnomad4 FIN exome AF: 0.0197

Gnomad4 NFE exome AF: 0.0308

Gnomad4 OTH exome AF: 0.0292

GnomAD4 genome AF: 0.0490 AC: 7458 AN: 152268 Hom.: 276 Cov.: 33 AF XY: 0.0474 AC XY: 3526 AN XY: 74450

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.0352

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00705

Gnomad4 FIN AF: 0.0237

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0393

Alfa AF: 0.0304 Hom.: 159

Bravo AF: 0.0527

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.0245

EpiControl AF: 0.0268

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2018

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 28, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4

May 29, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 25, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MCAD DEFICIENCY, MODIFIER OF Other:1

Mar 01, 2007

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.1
DANN	Benign	0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs74090726; hg19: chr1-76199277;