12-120725830-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000017.4(ACADS):c.-56C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000716 in 1,518,430 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00073 (11 hom.)
• Consequence: ACADS NM_000017.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.822

Genes affected

ACADS (HGNC:90): (acyl-CoA dehydrogenase short chain) This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Mutations in this gene have been associated with short-chain acyl-CoA dehydrogenase (SCAD) deficiency. Alternative splicing results in two variants which encode different isoforms. [provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACADS	NM_000017.4	c.-56C>G		5_prime_UTR_variant	1/10	ENST00000242592.9
ACADS	NM_001302554.2	c.-56C>G		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACADS	ENST00000242592.9	c.-56C>G		5_prime_UTR_variant	1/10	1	NM_000017.4	P1
ACADS	ENST00000539690.1	n.57C>G		non_coding_transcript_exon_variant	1/3	2
ACADS	ENST00000411593.2			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.000539 AC: 82 AN: 152080 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000735 AC: 1004 AN: 1366236 Hom.: 11 Cov.: 29 AF XY: 0.000942 AC XY: 636 AN XY: 674964

Gnomad4 AFR exome AF: 0.000174

Gnomad4 AMR exome AF: 0.000658

Gnomad4 ASJ exome AF: 0.00110

Gnomad4 EAS exome AF: 0.000500

Gnomad4 SAS exome AF: 0.00756

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.00110

GnomAD4 genome AF: 0.000545 AC: 83 AN: 152194 Hom.: 1 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74392

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00581

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.000397

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.76

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: rs567626964; hg19: chr12-121163633;