rs143911981

Positions:

• chr1-75762840-C-T

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.*77C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00665 in 891,436 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (74 hom.)
• Consequence: ACADM NM_000016.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.251

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=-0.89).
• BP6: Variant 1-75762840-C-T is Benign according to our data. Variant chr1-75762840-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADM	NM_000016.6	c.*77C>T		3_prime_UTR_variant	12/12	ENST00000370841.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADM	ENST00000370841.9	c.*77C>T		3_prime_UTR_variant	12/12	1	NM_000016.6	P4

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 996 AN: 152040 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00595

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00418

Gnomad OTH AF: 0.00720

GnomAD4 exome AF: 0.00667 AC: 4933 AN: 739278 Hom.: 74 Cov.: 10 AF XY: 0.00636 AC XY: 2480 AN XY: 389698

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.0651

Gnomad4 ASJ exome AF: 0.00503

Gnomad4 EAS exome AF: 0.000265

Gnomad4 SAS exome AF: 0.00519

Gnomad4 FIN exome AF: 0.00631

Gnomad4 NFE exome AF: 0.00424

Gnomad4 OTH exome AF: 0.00586

GnomAD4 genome AF: 0.00655 AC: 996 AN: 152158 Hom.: 16 Cov.: 33 AF XY: 0.00684 AC XY: 509 AN XY: 74378

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.0347

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00595

Gnomad4 NFE AF: 0.00418

Gnomad4 OTH AF: 0.00712

Alfa AF: 0.00610 Hom.: 2

Bravo AF: 0.00894

Asia WGS AF: 0.00667 AC: 23 AN: 3460

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Medium-chain acyl-coenzyme A dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 20, 2015	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.85
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs143911981; hg19: chr1-76228525;