chr3-128879647-C-CTAAG

Position:

chr3-128879647-C-CTAAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_014049.5(ACAD9):c.-44_-41dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,609,038 control chromosomes in the GnomAD database, including 1,480 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.050 ( 388 hom., cov: 32)

Exomes 𝑓: 0.021 ( 1092 hom. )

Consequence

ACAD9
NM_014049.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:7

Conservation

PhyloP100: -1.46

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 3-128879647-C-CTAAG is Benign according to our data. Variant chr3-128879647-C-CTAAG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1018.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0497 (7560/152226) while in subpopulation AFR AF= 0.124 (5135/41500). AF 95% confidence interval is 0.121. There are 388 homozygotes in gnomad4. There are 3832 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 388 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	#exon/exons	MANE
ACAD9	NM_014049.5 linkuse as main transcript	c.-44_-41dup	5_prime_UTR_variant	1/18	ENST00000308982.12
ACAD9	NM_001410805.1 linkuse as main transcript	c.-319_-316dup	5_prime_UTR_variant	1/17
ACAD9	NR_033426.2 linkuse as main transcript	n.29_32dup	non_coding_transcript_exon_variant	1/18
ACAD9	XR_427367.4 linkuse as main transcript	n.29_32dup	non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD9	ENST00000308982.12 linkuse as main transcript	c.-44_-41dup		5_prime_UTR_variant	1/18	1	NM_014049.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0496

AC:

7542

AN:

152108

Hom.:

385

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0239

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.0589

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.0384

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0316

GnomAD3 exomes

AF:

0.0374

AC:

9313

AN:

248930

Hom.:

395

AF XY:

0.0384

AC XY:

5196

AN XY:

135296

show subpopulations

Gnomad AFR exome

AF:

0.126

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.0221

Gnomad EAS exome

AF:

0.0632

Gnomad SAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.0422

Gnomad NFE exome

AF:

0.0115

Gnomad OTH exome

AF:

0.0245

GnomAD4 exome

AF:

0.0210

AC:

30580

AN:

1456812

Hom.:

1092

Cov.:

AF XY:

0.0229

AC XY:

16587

AN XY:

724872

show subpopulations

Gnomad4 AFR exome

AF:

0.132

Gnomad4 AMR exome

AF:

0.0127

Gnomad4 ASJ exome

AF:

0.0198

Gnomad4 EAS exome

AF:

0.0508

Gnomad4 SAS exome

AF:

0.102

Gnomad4 FIN exome

AF:

0.0409

Gnomad4 NFE exome

AF:

0.00933

Gnomad4 OTH exome

AF:

0.0293

GnomAD4 genome

AF:

0.0497

AC:

7560

AN:

152226

Hom.:

388

Cov.:

AF XY:

0.0515

AC XY:

3832

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.124

Gnomad4 AMR

AF:

0.0239

Gnomad4 ASJ

AF:

0.0150

Gnomad4 EAS

AF:

0.0588

Gnomad4 SAS

AF:

0.111

Gnomad4 FIN

AF:

0.0384

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.0308

Alfa

AF:

0.0248

Hom.:

Bravo

AF:

0.0504

Asia WGS

AF:

0.0890

AC:

311

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Acyl-CoA dehydrogenase 9 deficiency

Pathogenic:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, flagged submission	literature only	OMIM	Jul 01, 2007	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 23, 2020	Variant summary: ACAD9 c.-44_-41dupTAAG is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.039 in 280626 control chromosomes in the gnomAD database, including 475 homozygotes. The observed variant frequency is approximately 35 fold of the estimated maximal expected allele frequency for a pathogenic variant in ACAD9 causing Mitochondrial Complex I Deficiency, Nuclear Type 20 phenotype (0.0011), strongly suggesting that the variant is benign. c.-44_-41dupTAAG has been reported in the literature in one individual affected with Acyl-Coenzyme dehydrogenase 9 deficiency (He_2007). The report does not provide unequivocal conclusions about association of the variant with Mitochondrial Complex I Deficiency, Nuclear Type 20. He_2007 reports this variant results in a transcriptional defect from patients liver sample and 75% reduction of expression of a reporter gene. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Although the allele frequency of this variant suggests it may be benign, the possibility of it being a common low-penetrant pathogenic variant cannot be ruled out. Therefore, this variant was classified as VUS-possibly benign. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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