rs786204691

Variant names:

• chr12-120738335-AAG-A
• rs786204691
• NM_000017.4:c.682_683delGA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000017.4(ACADS):​c.682_683delGA​(p.Glu228ArgfsTer16) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: ACADS NM_000017.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.61
• Publications: 1 publications found

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]

ACADS Gene-Disease associations (from GenCC):

• short chain acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Orphanet, ClinGen

ENSG00000255946 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120738335-AAG-A is Pathogenic according to our data. Variant chr12-120738335-AAG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 189093.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.682_683delGA	p.Glu228ArgfsTer16	frameshift_variant	Exon 6 of 10	ENST00000242592.9	NP_000008.1
ACADS	NM_001302554.2	c.670_671delGA	p.Glu224ArgfsTer16	frameshift_variant	Exon 6 of 10		NP_001289483.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACADS	ENST00000242592.9	c.682_683delGA	p.Glu228ArgfsTer16	frameshift_variant	Exon 6 of 10	1	NM_000017.4	ENSP00000242592.4
ACADS	ENST00000411593.2	c.670_671delGA	p.Glu224ArgfsTer16	frameshift_variant	Exon 6 of 10	2		ENSP00000401045.2
ENSG00000255946	ENST00000724268.1	n.305-8049_305-8048delCT		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000315 AC: 46 AN: 1461868 Hom.: 0 AF XY: 0.0000344 AC XY: 25 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1112010

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:4

Apr 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with clinical features of ACADS-related conditions (PMID: 22241096). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189093). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu228Argfs*16) in the ACADS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACADS are known to be pathogenic (PMID: 12736383, 18523805). -

Dec 16, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACADS: PVS1, PM2, PM3:Supporting -

Apr 29, 2014

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.682_683delGA mutation in the ACADS gene has been reported previously in association with short chain acyl-CoA dehydrogenase deficiency (Pena et al., 2012). The deletion causes a frameshift starting with codon Glutamic Acid 228, changes this amino acid to an Arginine residue and creates a premature Stop codon at position 16 of the new reading frame, denoted p.Glu228ArgfsX16. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The surrounding sequence GAAA{delGA}AGAC. The variant is found in ACADS panel(s). -

ACADS-related disorder Pathogenic:1

Oct 20, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACADS c.682_683delGA variant is predicted to result in a frameshift and premature protein termination (p.Glu228Argfs*16). This variant was reported along with another potentially causative variant in an individual with short-chain acyl-CoA-dehydrogenase deficiency (Pena. 2012. PubMed ID: 22241096). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in ACADS are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204691; hg19: chr12-121176138;