rs863224844

Variant names:

• chr3-128895320-CT-C
• rs863224844
• NM_014049.5:c.359delT

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_014049.5(ACAD9):​c.359delT​(p.Phe120SerfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000819 in 1,611,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000915988: Mitochondrial respiratory chain complex I activity was reduced in patient-derived muscle and heart tissue (Collet et al. 2015" and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: ACAD9 NM_014049.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.57
• Publications: 5 publications found

Genes affected

ACAD9 (HGNC:21497): (acyl-CoA dehydrogenase family member 9) This gene encodes a member of the acyl-CoA dehydrogenase family. Members of this family of proteins localize to the mitochondria and catalyze the rate-limiting step in the beta-oxidation of fatty acyl-CoA. The encoded protein is specifically active toward palmitoyl-CoA and long-chain unsaturated substrates. Mutations in this gene cause acyl-CoA dehydrogenase family member type 9 deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

ACAD9 Gene-Disease associations (from GenCC):

• acyl-CoA dehydrogenase 9 deficiency

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000915988: Mitochondrial respiratory chain complex I activity was reduced in patient-derived muscle and heart tissue (Collet et al. 2015; Schiff et al. 2015; Fragaki et al. 2017).
• PP5: Variant 3-128895320-CT-C is Pathogenic according to our data. Variant chr3-128895320-CT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 242524.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014049.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	NM_014049.5	MANE Select	c.359delT	p.Phe120SerfsTer9	frameshift	Exon 4 of 18	NP_054768.2
	ACAD9	NM_001410805.1		c.-11delT		5_prime_UTR	Exon 3 of 17	NP_001397734.1	Q9H9W4
	ACAD9	NR_033426.2		n.607delT		non_coding_transcript_exon	Exon 4 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.359delT	p.Phe120SerfsTer9	frameshift	Exon 4 of 18	ENSP00000312618.7	Q9H845
	ACAD9	ENST00000681367.1		c.359delT	p.Phe120SerfsTer9	frameshift	Exon 4 of 19	ENSP00000505309.1	A0A7P0T8U3
	ACAD9	ENST00000680636.1		c.359delT	p.Phe120SerfsTer9	frameshift	Exon 4 of 18	ENSP00000504886.1	A0A7P0T7Z1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151884 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 247292 AF XY: 0.0000899

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.000525

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000357

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1459796 Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38 AN XY: 725916

African (AFR) AF: 0.00 AC: 0 AN: 33404

American (AMR) AF: 0.000494 AC: 22 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 85622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111102

Other (OTH) AF: 0.000149 AC: 9 AN: 60334

GnomAD4 genome AF: 0.000349 AC: 53 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.000566 AC XY: 42 AN XY: 74258

African (AFR) AF: 0.0000241 AC: 1 AN: 41414

American (AMR) AF: 0.00295 AC: 45 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 67990

Other (OTH) AF: 0.000477 AC: 1 AN: 2098

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000230

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Acyl-CoA dehydrogenase 9 deficiency (6)
2	-	-	not provided (2)
1	-	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs863224844; hg19: chr3-128614163;