3-128879696-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014049.5(ACAD9):c.5G>A(p.Ser2Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ACAD9 NM_014049.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.781

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16946778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACAD9	NM_014049.5	c.5G>A	p.Ser2Asn	missense_variant	1/18	ENST00000308982.12
ACAD9	NM_001410805.1	c.-271G>A		5_prime_UTR_variant	1/17
ACAD9	NR_033426.2	n.77G>A		non_coding_transcript_exon_variant	1/18
ACAD9	XR_427367.4	n.77G>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACAD9	ENST00000308982.12	c.5G>A	p.Ser2Asn	missense_variant	1/18	1	NM_014049.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248616 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134942

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460036 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726358

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2 of the ACAD9 protein (p.Ser2Asn). This variant is present in population databases (rs761385146, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ACAD9-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACAD9 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	0.96
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.38	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.20
Sift	Benign	0.068	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;.
Vest4		0.16
MutPred		0.16		Loss of glycosylation at S2 (P = 0.0264);Loss of glycosylation at S2 (P = 0.0264);
MVP		0.87
MPC		0.17
ClinPred		0.039	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.073
gMVP		0.34

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

Publications

LitVar

Other links and lift over

dbSNP: rs761385146; hg19: chr3-128598539;