Genetic Variant ACAD9:c.-168T>C (chr3-128879524-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014049.5(ACAD9):c.-168T>C variant causes a upstream gene 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
NM_014049.5 upstream_gene

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.19

Variant links:

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 links:

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

ACAD9-DT links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 343186.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD9	NM_014049.5 link	c.-168T>C		upstream_gene_variant		ENST00000308982.12	NP_054768.2	Q9H845

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982.12 link	c.-168T>C		upstream_gene_variant		1	NM_014049.5	ENSP00000312618.7		Q9H845

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1787

AN:

152162

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0128

AC:

2619

AN:

205274

Hom.:

AF XY:

0.0128

AC XY:

1445

AN XY:

113268

show subpopulations

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 SAS exome

AF:

0.00589

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.:

AF XY:

0.0138

AC XY:

5569

AN XY:

402912

show subpopulations

Gnomad4 AFR exome

AF:

0.00350

Gnomad4 AMR exome

AF:

0.0185

Gnomad4 ASJ exome

AF:

0.0295

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00674

Gnomad4 FIN exome

AF:

0.00302

Gnomad4 NFE exome

AF:

0.0159

Gnomad4 OTH exome

AF:

0.0168

GnomAD4 genome

AF:

0.0117

AC:

1787

AN:

152280

Hom.:

Cov.:

AF XY:

0.0107

AC XY:

800

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00347

Gnomad4 AMR

AF:

0.0215

Gnomad4 ASJ

AF:

0.0326

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00518

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.0162

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.0137

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acyl-CoA dehydrogenase 9 deficiency

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jun 28, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

5.4

DANN

Benign

0.34

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over