Genetic Variant NM_014049.5:c.3G>A (chr3-128879694-G-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_SupportingPM2PP5_Moderate

The NM_014049.5(ACAD9):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ACAD9
NM_014049.5 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.77

Variant links:

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 links:

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

ACAD9-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 124 codons. Genomic position: 128895333. Lost 0.198 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-128879694-G-A is Pathogenic according to our data. Variant chr3-128879694-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1451006.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACAD9	NM_014049.5 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 18	ENST00000308982.12	NP_054768.2	Q9H845
ACAD9	NM_001410805.1 link	c.-273G>A		5_prime_UTR_variant	Exon 1 of 17		NP_001397734.1
ACAD9	NR_033426.2 link	n.75G>A		non_coding_transcript_exon_variant	Exon 1 of 18
ACAD9	XR_427367.4 link	n.75G>A		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACAD9	ENST00000308982.12 link	c.3G>A	p.Met1?	start_lost	Exon 1 of 18	1	NM_014049.5	ENSP00000312618.7		Q9H845

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460096

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). Disruption of the initiator codon ‚Äãhas been observed in individual(s) with mitochondrial complex I deficiency (PMID: 26669660, 30025539). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant This variant disrupts the initiator methionine in ACAD9. If translation initiates from the next in-frame methionine, the ACAD9 protein would no longer include the region containing the p.Phe44 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with ACAD9-related conditions (PMID: 21057504), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the ACAD9 mRNA. The next in-frame methionine is located at codon p.Met124. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.64

PROVEAN

Benign

-0.61

N;N

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.067

T;D

Polyphen

0.92

P;.

Vest4

0.89

MutPred

0.98

Loss of disorder (P = 0.038);Loss of disorder (P = 0.038);

MVP

0.99

ClinPred

0.99

GERP RS

5.3

Varity_R

0.96

gMVP

0.63

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over