ENST00000692357.3:n.67A>G

Variant names:

• chr3-128879524-T-C
• rs183973851
• ENST00000692357.3:n.67A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000692357.3(ACAD9-DT):​n.67A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 922,810 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 34)
  • Exomes 𝑓: 0.014 (107 hom.)
• Consequence: ACAD9-DT ENST00000692357.3 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.19
• Publications: 4 publications found

Genes affected

ACAD9-DT (HGNC:56086): (ACAD9 divergent transcript)

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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 3-128879524-T-C is Benign according to our data. Variant chr3-128879524-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343186.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0117 (1787/152280) while in subpopulation AMR AF = 0.0215 (329/15306). AF 95% confidence interval is 0.0196. There are 21 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000692357.3. 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.-168T>C		upstream_gene	N/A	NP_054768.2
	ACAD9	NM_001410805.1		c.-443T>C		upstream_gene	N/A	NP_001397734.1	Q9H9W4
	ACAD9	NR_033426.2		n.-96T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9-DT	ENST00000692357.3		n.67A>G		non_coding_transcript_exon	Exon 1 of 1
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.-168T>C		upstream_gene	N/A	ENSP00000312618.7	Q9H845
	ACAD9	ENST00000681367.1		c.-168T>C		upstream_gene	N/A	ENSP00000505309.1	A0A7P0T8U3

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1787 AN: 152162 Hom.: 21 Cov.: 34

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0163

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0128 AC: 2619 AN: 205274 AF XY: 0.0128

Gnomad AFR exome AF: 0.00341

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0285

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00232

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0139 AC: 10744 AN: 770530 Hom.: 107 Cov.: 10 AF XY: 0.0138 AC XY: 5569 AN XY: 402912

African (AFR) AF: 0.00350 AC: 72 AN: 20586

American (AMR) AF: 0.0185 AC: 770 AN: 41580

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 580 AN: 19688

East Asian (EAS) AF: 0.00 AC: 0 AN: 36242

South Asian (SAS) AF: 0.00674 AC: 459 AN: 68132

European-Finnish (FIN) AF: 0.00302 AC: 112 AN: 37034

Middle Eastern (MID) AF: 0.0269 AC: 74 AN: 2756

European-Non Finnish (NFE) AF: 0.0159 AC: 8047 AN: 507058

Other (OTH) AF: 0.0168 AC: 630 AN: 37454

GnomAD4 genome AF: 0.0117 AC: 1787 AN: 152280 Hom.: 21 Cov.: 34 AF XY: 0.0107 AC XY: 800 AN XY: 74456

African (AFR) AF: 0.00347 AC: 144 AN: 41536

American (AMR) AF: 0.0215 AC: 329 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0326 AC: 113 AN: 3470

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

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0162 AC: 1105 AN: 68034

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0151 Hom.: 9

Bravo AF: 0.0137

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Acyl-CoA dehydrogenase 9 deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	5.4
DANN	Benign	0.34
PhyloP100		-1.2
PromoterAI		0.31	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs183973851; hg19: chr3-128598367; COSMIC: COSV58307194;