chr3-128879694-G-A

Variant names:

• chr3-128879694-G-A
• rs2107636803
• NM_014049.5:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.77
• Publications: 0 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: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 25 pathogenic variants. Next in-frame start position is after 124 codons. Genomic position: 128895333. Lost 0.198 part of the original CDS.
• PS1: Another start lost variant in NM_014049.5 (ACAD9) was described as [Pathogenic] in ClinVar
• 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 VariationId is 1451006.Status of the report is criteria_provided_single_submitter, 1 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	NM_014049.5	MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 18	NP_054768.2
	ACAD9	NM_001410805.1		c.-273G>A		5_prime_UTR	Exon 1 of 17	NP_001397734.1	Q9H9W4
	ACAD9	NR_033426.2		n.75G>A		non_coding_transcript_exon	Exon 1 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.3G>A	p.Met1?	start_lost	Exon 1 of 18	ENSP00000312618.7	Q9H845
	ACAD9	ENST00000681367.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 19	ENSP00000505309.1	A0A7P0T8U3
	ACAD9	ENST00000680636.1		c.3G>A	p.Met1?	start_lost	Exon 1 of 18	ENSP00000504886.1	A0A7P0T7Z1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460096 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726390

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111854

Other (OTH) AF: 0.0000332 AC: 2 AN: 60262

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.64	D
PhyloP100		2.8
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.067	T
Polyphen		0.92	P
Vest4		0.89
MutPred		0.98		Loss of disorder (P = 0.038)
MVP		0.99
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.080	Neutral
Varity_R		0.96
gMVP		0.63
Mutation Taster		=15/185	disease causing

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: rs2107636803; hg19: chr3-128598537;