3-128879647-C-CTAAG

Position:

• chr3-128879647-C-CTAAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:7
• Conservation: PhyloP100: -1.46

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]

ACMG classification

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	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD9	NM_014049.5	c.-44_-41dup		5_prime_UTR_variant	1/18	ENST00000308982.12
ACAD9	NM_001410805.1	c.-319_-316dup		5_prime_UTR_variant	1/17
ACAD9	NR_033426.2	n.29_32dup		non_coding_transcript_exon_variant	1/18
ACAD9	XR_427367.4	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	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.: 32

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

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.: 30 AF XY: 0.0229 AC XY: 16587 AN XY: 724872

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.: 32 AF XY: 0.0515 AC XY: 3832 AN XY: 74448

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.: 20

Bravo AF: 0.0504

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acyl-CoA dehydrogenase 9 deficiency Pathogenic:1 Benign: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:1 Benign: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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs387906242; hg19: chr3-128598490;