1-75724754-T-C

Position:

• chr1-75724754-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.-34T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0311 in 1,535,728 control chromosomes in the GnomAD database, including 1,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (278 hom., cov: 32)
  • Exomes 𝑓: 0.029 (808 hom.)
• Consequence: ACADM NM_000016.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.21

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=-0.84).
• BP6: Variant 1-75724754-T-C is Benign according to our data. Variant chr1-75724754-T-C is described in ClinVar as [Benign]. Clinvar id is 136258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
ACADM	NM_000016.6	c.-34T>C		5_prime_UTR_variant	1/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.-34T>C		5_prime_UTR_variant	1/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.0490 AC: 7455 AN: 152110 Hom.: 276 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0350

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00704

Gnomad FIN AF: 0.0235

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0401

GnomAD3 exomes AF: 0.0258 AC: 4923 AN: 190664 Hom.: 105 AF XY: 0.0240 AC XY: 2497 AN XY: 104152

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.0220

Gnomad ASJ exome AF: 0.00416

Gnomad EAS exome AF: 0.0000885

Gnomad SAS exome AF: 0.00768

Gnomad FIN exome AF: 0.0197

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.0273

GnomAD4 exome AF: 0.0292 AC: 40330 AN: 1383500 Hom.: 808 Cov.: 30 AF XY: 0.0282 AC XY: 19359 AN XY: 685884

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0240

Gnomad4 ASJ exome AF: 0.00412

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00783

Gnomad4 FIN exome AF: 0.0193

Gnomad4 NFE exome AF: 0.0307

Gnomad4 OTH exome AF: 0.0289

GnomAD4 genome AF: 0.0491 AC: 7471 AN: 152228 Hom.: 278 Cov.: 32 AF XY: 0.0475 AC XY: 3537 AN XY: 74436

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.0235

Gnomad4 NFE AF: 0.0297

Gnomad4 OTH AF: 0.0397

Alfa AF: 0.0337 Hom.: 47

Bravo AF: 0.0528

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Eurofins Ntd Llc (ga)	Oct 01, 2015	- -

Medium-chain acyl-coenzyme A dehydrogenase deficiency Benign:3

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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 15, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs59932454; hg19: chr1-76190439; COSMIC: COSV63720157; COSMIC: COSV63720157;