rs1057516421

Variant names:

• chr12-120739372-CTG-C
• rs1057516421
• NM_000017.4:c.1164_1165delTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000017.4(ACADS):​c.1164_1165delTG​(p.Glu389AspfsTer101) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ACADS NM_000017.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.61

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0605 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120739372-CTG-C is Pathogenic according to our data. Variant chr12-120739372-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACADS	NM_000017.4	c.1164_1165delTG	p.Glu389AspfsTer101	frameshift_variant	Exon 10 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.1152_1153delTG	p.Glu385AspfsTer101	frameshift_variant	Exon 10 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.1164_1165delTG	p.Glu389AspfsTer101	frameshift_variant	Exon 10 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.1152_1153delTG	p.Glu385AspfsTer73	frameshift_variant	Exon 10 of 10	2		ENSP00000401045.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000805 AC: 2 AN: 248320 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135098

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460624 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 726652

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:2

Jan 18, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the ACADS gene (p.Glu389Aspfs*101). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the ACADS protein and extend the protein by 76 additional amino acid residues. This variant is present in population databases (no rsID available, gnomAD 0.006%). This frameshift has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 370351). This variant disrupts a region of the ACADS protein in which other variant(s) (p.Gln398*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057516421; hg19: chr12-121177175;