rs17848065

Positions:

• chr1-75762802-G-A

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.*39G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,288,190 control chromosomes in the GnomAD database, including 1,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (140 hom., cov: 33)
  • Exomes 𝑓: 0.036 (890 hom.)
• Consequence: ACADM NM_000016.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.92

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=-0.82).
• BP6: Variant 1-75762802-G-A is Benign according to our data. Variant chr1-75762802-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.*39G>A		3_prime_UTR_variant	12/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.*39G>A		3_prime_UTR_variant	12/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5972 AN: 151974 Hom.: 141 Cov.: 33

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0332

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0590

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0403

Gnomad OTH AF: 0.0412

GnomAD3 exomes AF: 0.0355 AC: 7969 AN: 224584 Hom.: 193 AF XY: 0.0355 AC XY: 4340 AN XY: 122252

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.0230

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.00604

Gnomad SAS exome AF: 0.0334

Gnomad FIN exome AF: 0.0591

Gnomad NFE exome AF: 0.0404

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0360 AC: 40866 AN: 1136098 Hom.: 890 Cov.: 15 AF XY: 0.0361 AC XY: 20930 AN XY: 579168

Gnomad4 AFR exome AF: 0.0368

Gnomad4 AMR exome AF: 0.0247

Gnomad4 ASJ exome AF: 0.0307

Gnomad4 EAS exome AF: 0.00554

Gnomad4 SAS exome AF: 0.0307

Gnomad4 FIN exome AF: 0.0599

Gnomad4 NFE exome AF: 0.0368

Gnomad4 OTH exome AF: 0.0374

GnomAD4 genome AF: 0.0393 AC: 5974 AN: 152092 Hom.: 140 Cov.: 33 AF XY: 0.0393 AC XY: 2919 AN XY: 74368

Gnomad4 AFR AF: 0.0365

Gnomad4 AMR AF: 0.0380

Gnomad4 ASJ AF: 0.0332

Gnomad4 EAS AF: 0.00560

Gnomad4 SAS AF: 0.0313

Gnomad4 FIN AF: 0.0590

Gnomad4 NFE AF: 0.0403

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0381 Hom.: 39

Bravo AF: 0.0371

Asia WGS AF: 0.0250 AC: 86 AN: 3470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely 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	-0.82
CADD	Benign	0.15
DANN	Benign	0.52

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: rs17848065; hg19: chr1-76228487;