rs377022708

Variant names:

• chr3-128910051-C-T
• rs377022708
• NM_014049.5:c.1594C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_014049.5(ACAD9):​c.1594C>T​(p.Arg532Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,724 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000251037: Functional studies comparing wildtype and mutant ACAD9 indicate the R532W variant is unable to restore complex 1 activity in mutant cell lines (Gerards et al., 2011)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R532L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ACAD9 NM_014049.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.28
• Publications: 14 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]

CFAP92 (HGNC:29231): (cilia and flagella associated protein 92 (putative))

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000251037: Functional studies comparing wildtype and mutant ACAD9 indicate the R532W variant is unable to restore complex 1 activity in mutant cell lines (Gerards et al., 2011).; SCV002103862: Experimental evidence shows the variant to exhibit ACAD9 activity indistinguishable from wild type, leading authors to suggest that mutations in ACAD9 lead to CI deficiency independent of their effects on ACAD enzyme activity (Schiff_2015).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-128910052-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3767183.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 3-128910051-C-T is Pathogenic according to our data. Variant chr3-128910051-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1594C>T	p.Arg532Trp	missense	Exon 16 of 18	NP_054768.2
	CFAP92	NM_001394090.1	MANE Select	c.*248G>A		3_prime_UTR	Exon 16 of 16	NP_001381019.1	A0A2R8YFM9
	ACAD9	NM_001410805.1		c.1225C>T	p.Arg409Trp	missense	Exon 15 of 17	NP_001397734.1	Q9H9W4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACAD9	ENST00000308982.12	TSL:1 MANE Select	c.1594C>T	p.Arg532Trp	missense	Exon 16 of 18	ENSP00000312618.7	Q9H845
	CFAP92	ENST00000645291.3	MANE Select	c.*248G>A		3_prime_UTR	Exon 16 of 16	ENSP00000496592.2	A0A2R8YFM9
	ACAD9	ENST00000511526.5	TSL:1	n.1127C>T		non_coding_transcript_exon	Exon 12 of 14

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000253 AC: 37 AN: 1461546 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727046

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1111950

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000136 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Acyl-CoA dehydrogenase 9 deficiency (2)
2	-	-	not provided (2)
1	-	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.3
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MVP		0.97
MPC		0.75
ClinPred		1.0	D
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.91
Mutation Taster		=31/69	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377022708; hg19: chr3-128628894;