chr3-128879647-C-CTAAG

Variant names:

• chr3-128879647-C-CTAAG
• rs387906242
• NM_014049.5:c.-44_-41dupTAAG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_014049.5(ACAD9):​c.-44_-41dupTAAG 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:8
• 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]

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

ACMG classification

Our verdict: Benign. The variant received -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: {Uncertain_significance=1, Pathogenic=1, Likely_benign=2, Benign=3}.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 388 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD9	NM_014049.5	c.-44_-41dupTAAG		5_prime_UTR_variant	Exon 1 of 18	ENST00000308982.12	NP_054768.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982	c.-44_-41dupTAAG		5_prime_UTR_variant	Exon 1 of 18	1	NM_014049.5	ENSP00000312618.7

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

GnomAD2 exomes AF: 0.0374 AC: 9313 AN: 248930 AF XY: 0.0384

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 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 AC: 4395 AN: 33336

Gnomad4 AMR exome AF: 0.0127 AC: 566 AN: 44706

Gnomad4 ASJ exome AF: 0.0198 AC: 516 AN: 26110

Gnomad4 EAS exome AF: 0.0508 AC: 2014 AN: 39668

Gnomad4 SAS exome AF: 0.102 AC: 8769 AN: 86100

Gnomad4 FIN exome AF: 0.0409 AC: 2160 AN: 52868

Gnomad4 NFE exome AF: 0.00933 AC: 10350 AN: 1109726

Gnomad4 Remaining exome AF: 0.0293 AC: 1761 AN: 60118

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 AC: 0.123735 AN: 0.123735

Gnomad4 AMR AF: 0.0239 AC: 0.0238624 AN: 0.0238624

Gnomad4 ASJ AF: 0.0150 AC: 0.0149856 AN: 0.0149856

Gnomad4 EAS AF: 0.0588 AC: 0.0588463 AN: 0.0588463

Gnomad4 SAS AF: 0.111 AC: 0.111433 AN: 0.111433

Gnomad4 FIN AF: 0.0384 AC: 0.0384108 AN: 0.0384108

Gnomad4 NFE AF: 0.0101 AC: 0.0101429 AN: 0.0101429

Gnomad4 OTH AF: 0.0308 AC: 0.0308057 AN: 0.0308057

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:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Acyl-CoA dehydrogenase 9 deficiency Pathogenic:1 Benign:4

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2007

OMIM

Significance: Pathogenic

Review Status: flagged submission

Collection Method: literature only

- -

Apr 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Sep 23, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=300/0	polymorphism (auto)

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;