NM_014049.5:c.130T>A

Variant names:

• chr3-128879821-T-A
• rs387907041
• NM_014049.5:c.130T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_014049.5(ACAD9):​c.130T>A​(p.Phe44Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACAD9 NM_014049.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.49
• Publications: 5 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8
• PP5: Variant 3-128879821-T-A is Pathogenic according to our data. Variant chr3-128879821-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30881.Status of the report is no_assertion_criteria_provided, 0 stars.

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.130T>A	p.Phe44Ile	missense	Exon 1 of 18	NP_054768.2
	ACAD9	NR_033426.2		n.202T>A		non_coding_transcript_exon	Exon 1 of 18
	ACAD9	NM_001410805.1		c.-146T>A		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.130T>A	p.Phe44Ile	missense	Exon 1 of 18	ENSP00000312618.7
	ACAD9	ENST00000681367.1		c.130T>A	p.Phe44Ile	missense	Exon 1 of 19	ENSP00000505309.1
	ACAD9	ENST00000680636.1		c.130T>A	p.Phe44Ile	missense	Exon 1 of 18	ENSP00000504886.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Acyl-CoA dehydrogenase 9 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.5
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.97	D
Vest4		0.58
MutPred		0.37		Gain of helix (P = 0.027)
MVP		0.98
MPC		0.31
ClinPred		1.0	D
GERP RS		5.6
PromoterAI		0.075	Neutral
Varity_R		0.85
gMVP		0.91
Mutation Taster		=24/76	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs387907041; hg19: chr3-128598664;