NM_014049.5:c.-44_-41dupTAAG

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
• Publications: 2 publications found

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 VariationId is 1018.
• 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 passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 388 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014049.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	NM_014049.5	MANE Select	c.-44_-41dupTAAG		5_prime_UTR	Exon 1 of 18	NP_054768.2
	ACAD9	NR_033426.2		n.29_32dupTAAG		non_coding_transcript_exon	Exon 1 of 18
	ACAD9	NM_001410805.1		c.-319_-316dupTAAG		5_prime_UTR	Exon 1 of 17	NP_001397734.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.-44_-41dupTAAG		5_prime_UTR	Exon 1 of 18	ENSP00000312618.7
	ACAD9	ENST00000505192.5	TSL:2	n.-44_-41dupTAAG		non_coding_transcript_exon	Exon 1 of 12	ENSP00000426277.1
	ACAD9	ENST00000505602.1	TSL:4	n.53_56dupTAAG		non_coding_transcript_exon	Exon 1 of 2

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

African (AFR) AF: 0.132 AC: 4395 AN: 33336

American (AMR) AF: 0.0127 AC: 566 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0198 AC: 516 AN: 26110

East Asian (EAS) AF: 0.0508 AC: 2014 AN: 39668

South Asian (SAS) AF: 0.102 AC: 8769 AN: 86100

European-Finnish (FIN) AF: 0.0409 AC: 2160 AN: 52868

Middle Eastern (MID) AF: 0.0117 AC: 49 AN: 4180

European-Non Finnish (NFE) AF: 0.00933 AC: 10350 AN: 1109726

Other (OTH) 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

African (AFR) AF: 0.124 AC: 5135 AN: 41500

American (AMR) AF: 0.0239 AC: 365 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3470

East Asian (EAS) AF: 0.0588 AC: 304 AN: 5166

South Asian (SAS) AF: 0.111 AC: 538 AN: 4828

European-Finnish (FIN) AF: 0.0384 AC: 408 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 690 AN: 68028

Other (OTH) AF: 0.0308 AC: 65 AN: 2110

Alfa AF: 0.0248 Hom.: 20

Bravo AF: 0.0504

Asia WGS AF: 0.0890 AC: 311 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	4	Acyl-CoA dehydrogenase 9 deficiency (5)
-	-	3	not provided (3)
-	1	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs387906242; hg19: chr3-128598490;